Substituted benz-azoles and methods of their use as inhibitors of raf kinase

ABSTRACT

New substituted benz-azole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/282,939, filed Nov. 18, 2005, which is a division of U.S. applicationSer. No. 10/405,945 (now U.S. Pat. No. 7,071,216), filed Mar. 31, 2003,which claims the benefit of U.S. Provisional Application No. 60/369,066,filed Mar. 29, 2002, each of which is incorporated herein by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to new substituted benz-azole-likecompounds and pharmaceutically acceptable salts, esters or prodrugsthereof, compositions of the new compounds together withpharmaceutically acceptable carriers, and uses of the new compounds,either alone or in combination with at least one additional therapeuticagent, in the prophylaxis or treatment of cancer.

BACKGROUND OF THE INVENTION

The Raf serine/threonine kinases are essential components of theRas/Mitogen-Activated Protein Kinase (MAPK) signaling module thatcontrols a complex transcriptional program in response to externalcellular stimuli. Raf genes code for highly conservedserine-threonine-specific protein kinases which are known to bind to theras oncogene. They are part of a signal transduction pathway believed toconsist of receptor tyrosine kinases, p21 ras, Raf protein kinases, Mek1(ERK activator or MAPKK) kinases and ERK (MAPK) kinases, whichultimately phosphorylate transcription factors. In this pathway Rafkinases are activated by Ras and phosphorylate and activate two isoformsof Mitogen-Activated Protein Kinase (called Mek1 and Mek2), that aredual specificity threonine/tyrosine kinases. Both Mek isoforms activateMitogen Activated Kinases 1 and 2 (MAPK, also called ExtracellularLigand Regulated Kinase 1 and 2 or Erk1 and Erk2). The MAPKsphosphorylate many substrates including transcription factors and in sodoing set up their transcriptional program. Raf kinase participation inthe Ras/MAPK pathway influences and regulates many cellular functionssuch as proliferation, differentiation, survival, oncogenictransformation and apoptosis.

Both the essential role and the position of Raf in many signalingpathways have been demonstrated from studies using deregulated anddominant inhibitory Raf mutants in mammalian cells as well as fromstudies employing biochemical and genetic techniques model organisms. Inmany cases, the activation of Raf by receptors that stimulate cellulartyrosine phosphorylation is dependent on the activity of Ras, indicatingthat Ras functions upstream of Raf. Upon activation, Raf-1 thenphosphorylates and activates Mek1, resulting in the propagation of thesignal to downstream effectors, such as MAPK (mitogen-activated proteinkinase) (Crews et al. (1993) Cell 74:215). The Raf serine/threoninekinases are considered to be the primary Ras effectors involved in theproliferation of animal cells (Avruch et al. (1994) Trends Biochem. Sci.19:279).

Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf,distinguished by their ability to interact with Ras, to activate MAPKkinase pathway, tissue distribution and sub-cellular localization(Marias et. Al., Biochem. J. 351: 289-305, 2000; Weber et. al., Oncogene19:169-176, 2000; Pritchard et. al., Mol. Cell. Biol. 15:6430-6442,1995). Raf kinases are activated by Ras and phosphorylate and activatetwo isoforms of Mitogen-Activated Protein Kinase (called Mek1 and Mek2)that are dual specificity threonine/tyrosine kinases. Both Mek isoformsactivate Mitogen Activated Kinases 1 and 2 (MAPK, also calledExtracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). TheMAPKs phosphorylate many substrates including cytosolic proteins and ETSfamily of transcription factors. Raf kinase participation in theRas/MAPK pathway influences and regulates many cellular functions suchas proliferation, differentiation, survival, cell cycle progression andapoptosis.

Activating mutation of one of the Ras genes can be seen in ˜20% of alltumors and the Raf/MEK/ERK pathway is activated in ˜30% of all tumors(Bos et. al., Cancer Res. 49:4682-4689, 1989) (Hoshino et. al., Oncogene18:813-822, 1999). Recent studies have shown that B-Raf mutation in theskin nevi is a critical step in the initiation of melanocytic neoplasia(Pollock et. al., Nature Genetics 25: 1-2, 2002). Furthermore, mostrecent studies have emerged that activating mutation in the kinasedomain of B-Raf occurs in ˜66% of melanomas, 12% of colon carcinoma and14% of liver cancer (Davies et. al., Nature 417:949-954, 2002) (Yuen et.al., Cancer Research 62:6451-6455, 2002) (Brose et. al., Cancer Research62:6997-7000, 2002).

Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases canpotentially be effective as therapeutic agents against tumors withover-expressed or mutated receptor tyrosine kinases, activatedintracellular tyrosine kinases, tumors with aberrantly expressed Grb2(an adapter protein that allows stimulation of Ras by the Sos exchangefactor) as well as tumors harboring activating mutations of Raf itself.In the early clinical trails inhibitor of Raf-1 kinase that also inhibitB-Raf have shown promise as therapeutic agents in cancer therapy (Crump,Current Pharmaceutical Design 8: 2243-2248, 2002; Sebastien et. al.,Current Pharmaceutical Design 8: 2249-2253, 2002).

Disruption of Raf expression in cell lines through the application ofRNA antisense technology has been shown to suppress both Ras andRaf-mediated tumorigenicity (Kolch et al., Nature 349:416-428, 1991;Monia et al., Nature Medicine 2(6):668-675, 1996).

Several Raf kinase inhibitors have been described as exhibiting efficacyin inhibiting tumor cell proliferation in vitro and/or in vivo assays(see, e.g., U.S. Pat. Nos. 6,391,636, 6,358,932, 6,037,136, 5,717,100,6,458,813, 6,204,467, and 6,268,391). Other patents and patentapplications suggest the use of Raf kinase inhibitors for treatingleukemia (see, e.g., U.S. Pat. Nos. 6,268,391, and 6,204,467, andpublished U.S. Patent Application Nos. 20020137774; 20020082192;20010016194; and 20010006975), or for treating breast cancer (see, e.g.,U.S. Pat. Nos. 6,358,932, 5,717,100, 6,458,813, 6,268,391, and6,204,467, and published U.S. Patent Application No. 20010014679).

SUMMARY OF THE INVENTION

New substituted benz-azole compounds and pharmaceutically acceptablesalts thereof or esters having a solubility enhancing moieties orprodrugs thereof are provided of the formula (I):

wherein, X₁ and X₂ are independently selected from ═N—, —NR₄—, —O— or—S—, provided that if X₁ is —NR₄—, —O— or —S—, then X₂ is ═N—, or if X₂is —NR₄—, —O— or —S—, then X₂ is ═N—, and both X₁ and X₂ are not ═N—;

Y is O or S;

A₁ is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl,aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl,heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, orheteroarylarylalkyl;

A₂ is substituted or unsubstituted heteroaryl;

R₁ is O or H, and R₂ is NR₅R₆ or hydroxyl; or R₁ is taken together withR₂ to form a substituted or unsubstituted heterocycloalkyl or heteroarylgroup; wherein, the dashed line represents a single or double bond;

R₃ is hydrogen, halogen, loweralkyl, or loweralkoxy;

R₄ is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;

R₅ and R₆ are independently selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R₅ and R₆ are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;and

the pharmaceutically acceptable salts, esters and prodrugs thereof.

In other embodiments, new substituted benz-azole compounds are providedof the formula (II):

wherein and Y, Ar₁, Ar₂, R₁, R₂, R₃ and R₄ are as defined above; and

the pharmaceutically acceptable salts, esters, and prodrugs thereof.

In other embodiments, new substituted benz-azole compounds are providedof the formula (III):

wherein X₁, Ar₁, Ar₂, R₁, R₂ and R₃ are as defined above; and

the pharmaceutically acceptable salts, esters, tautomers and prodrugsthereof.

In other embodiments, new substituted benz-azole compounds are providedof the formula (IV):

wherein X₁, Y, Ar₁, R₁, R₂ and R₃ are as defined above; and

the pharmaceutically acceptable salts, esters, tautomers and prodrugsthereof.

In yet other embodiments, new substituted benz-azole compounds areprovided of the formula (V):

wherein X₁, Ar₁, R₁, R₂ and R₃ are as defined above; and

the pharmaceutically acceptable salts, esters, tautomers and prodrugsthereof.

In other aspects, the present invention provides methods for treatingRaf related disorders in a human or animal subject in need of suchtreatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject.

In yet other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject in combination with at least oneadditional agent for the treatment of cancer.

In yet other aspects, the present invention provides therapeuticcompositions comprising at least one compound of formula (I), (II),(III), (IV) or (V) in combination with one or more additional agents forthe treatment of cancer, as are commonly employed in cancer therapy.

The compounds of the invention are useful in the treatment of cancers,including carcinomas (e.g., of the lungs, pancreas, thyroid, bladder orcolon), myeloid disorders (e.g., myeloid leukemia) and adenomas (e.g.,villous colon adenoma).

The invention further provides compositions, methods of use, and methodsof manufacture as described in the detailed description of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In accordance with one aspect of the present invention, new substitutedbenz-azole compounds and pharmaceutically acceptable salts, esters orprodrugs thereof are provided of the formula (I):

wherein, X₁ and X₂ are independently selected from ═N—, —NR₄—, —O— or—S—, provided that if X₁ is —NR₄—, —O— or —S—, then X₂ is ═N—, or if X₂is —NR₄—, —O— or —S—, then X₂ is ═N—, and both X₁ and X₂ are not ═N—; Yis O or S;

Y is O or S;

A₁ is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl,aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl,heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, orheteroarylarylalkyl;

A₂ is substituted or unsubstituted heteroaryl;

R₁ is O or H, and R₂ is NR₅R₆ or hydroxyl; or R₁ is taken together withR₂ to form a substituted or unsubstituted heterocycloalkyl or heteroarylgroup; wherein, the dashed line represents a single or double bond;

R₃ is hydrogen, halogen, loweralkyl, or loweralkoxy;

R₄ is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;

R₅ and R₆ are independently selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R₅ and R₆ are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;and

the pharmaceutically acceptable salts, esters and prodrugs thereof.

In other embodiments, new substituted benz-azole compounds are providedof the formula (II):

wherein and Y, Ar₁, Ar₂, R₁, R₂, R₃ and R₄ are as defined above; and

the pharmaceutically acceptable salts, esters, and prodrugs thereof.

In other embodiments, new substituted benz-azole compounds are providedof the formula (III):

wherein X₁, Ar₁, Ar₂, R₁, R₂ and R₃ are as defined above; and

the pharmaceutically acceptable salts, esters, tautomers and prodrugsthereof.

In other embodiments, new substituted benz-azole compounds are providedof the formula (IV):

wherein X₁, Y, Ar₁, R₁, R₂ and R₃ are as defined above; and

the pharmaceutically acceptable salts, esters, tautomers and prodrugsthereof.

In yet other embodiments, new substituted benz-azole compounds areprovided of the formula (V):

wherein X₁, Ar₁, R₁, R₂ and R₃ are as defined above; and

the pharmaceutically acceptable salts, esters, tautomers and prodrugsthereof.

In another aspect, the present invention provides methods of treatinghuman or animal subjects suffering from a Raf related disorder, such ascancer. Thus, the present invention provides methods of treating a humanor animal subject in need of such treatment comprising administering tothe subject a therapeutically effective amount of a compound of formulaI, II, III, IV or V above, either alone or in combination with otheranticancer agents.

In other aspects, the present invention provides methods for treatingRaf related disorders in a human or animal subject in need of suchtreatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject.

In yet other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject in combination with at least oneadditional agent for the treatment of cancer. A number of suitableanticancer agents to be used as combination therapeutics arecontemplated for use in the methods of the present invention. Indeed,the present invention contemplates, but is not limited to,administration of numerous anticancer agents such as: agents that induceapoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g.,enzymes); drugs; biological mimetics; alkaloids; alkylating agents;antitumor antibiotics; antimetabolites; hormones; platinum compounds;monoclonal antibodies conjugated with anticancer drugs, toxins, and/orradionuclides; biological response modifiers (e.g. interferons [e.g.IFN-a, etc.] and interleukins [e.g. IL-2, etc.], etc.); adoptiveimmunotherapy agents; hematopoietic growth factors; agents that inducetumor cell differentiation (e.g. all-trans-retinoic acid, etc.); genetherapy reagents; antisense therapy reagents and nucleotides; tumorvaccines; inhibitors of angiogenesis, and the like. Numerous otherexamples of chemotherapeutic compounds and anticancer therapies suitablefor coadministration with the disclosed compounds of formula (I), (II),(III), (IV) or (V) are known to those skilled in the art.

In preferred embodiments, anticancer agents to be used in combinationwith compounds of the present invention comprise agents that induce orstimulate apoptosis. Agents that induce apoptosis include, but are notlimited to, radiation (e.g., W); kinase inhibitors (e.g., EpidermalGrowth Factor Receptor [EGFR] kinase inhibitor, Vascular Growth FactorReceptor [VGFR] kinase inhibitor, Fibroblast Growth Factor Receptor[FGFR] kinase inhibitor, Platelet-derived Growth Factor Receptor [PGFR]I kinase inhibitor, and Bcr-Ab1 kinase inhibitors such as STI-571,Gleevec, and Glivec]); antisense molecules; antibodies [e.g., Herceptinand Rituxan]; anti-estrogens [e.g., raloxifene and tamoxifen];anti-androgens [e.g., flutamide, bicalutamide, finasteride,amino-glutethamide, ketoconazole, and corticosteroids]; cyclooxygenase 2(COX-2) inhibitors [e.g., Celecoxib, meloxicam, NS-398, andnon-steroidal antiinflammatory drugs (NSAIDs)]; and cancerchemotherapeutic drugs [e.g., irinotecan (Camptosar), CPT-11,fludarabine (Fludara), dacarbazine (DTIC), dexamethasone, mitoxantrone,Mylotarg, VP-16, cisplatinum, 5-FU, Doxrubicin, Taxotere or taxol];cellular signaling molecules; ceramides and cytokines; and staurosprine,and the like.

In other aspects, the present invention provides pharmaceuticalcompositions comprising at least one compound of formula I, II, III, IVor V together with a pharmaceutically acceptable carrier suitable foradministration to a human or animal subject, either alone or togetherwith other anticancer agents.

In other aspects, the present invention provides methods of manufactureof compounds of formula I, II, III, IV or V as described herein.

In yet other aspects, the present invention provides compounds which areinhibitors of the enzyme raf kinase. Since the enzyme is a downstreameffector of p21^(ras), the instant inhibitors are useful inpharmaceutical compositions for human or veterinary use where inhibitionof the raf kinase pathway is indicated, e.g., in the treatment of tumorsand/or cancerous cell growth mediated by raf kinase. In particular, thecompounds are useful in the treatment of human or animal, e.g., murinecancer, since the progression of these cancers is dependent upon the rasprotein signal transduction cascade and therefore is susceptible totreatment by interruption of the cascade by inhibiting raf kinaseactivity. Accordingly, the compounds of the invention are useful intreating solid cancers, such as, for example, carcinomas (e.g., of thelungs, pancreas, thyroid, bladder or colon, myeloid disorders (e.g.,myeloid leukemia) or adenomas (e.g., villous colon adenoma).

“Raf inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to Raf Kinase activity of no more than about 100 μMand more typically not more than about 50 μM, as measured in the Raf/MekFiltration Assay described generally hereinbelow. Preferred isoforms ofRaf Kinase in which the compounds of the present invention will be shownto inhibit, include A-Raf, B-Raf, and C-Raf (Raf-1). “IC₅₀” is thatconcentration of inhibitor which reduces the activity of an enzyme(e.g., Raf kinase) to half-maximal level. Representative compounds ofthe present invention have been discovered to exhibit inhibitoryactivity against Raf. Compounds of the present invention preferablyexhibit an IC₅₀ with respect to Raf of no more than about 10 μM, morepreferably, no more than about 5 μM, even more preferably not more thanabout 1 μM, and most preferably, not more than about 200 nM, as measuredin the Raf kinase assays described herein.

As used herein, the term “benz-azoles” includes benzimidazoles,benzothiazoles and benzoxazoles.

The phrase “alkyl” refers to alkyl groups that do not containheteroatoms. Thus the phrase includes straight chain alkyl groups suchas methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl and the like. The phrase also includes branchedchain isomers of straight chain alkyl groups, including but not limitedto, the following which are provided by way of example: —CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂,—CH₂CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃,—CH(CH₃)CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃,—CH(CH₃)CH₂—CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂,—CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others. The phrase also includescyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted withstraight and branched chain alkyl groups as defined above. Thus thephrase alkyl groups includes primary alkyl groups, secondary alkylgroups, and tertiary alkyl groups. Preferred alkyl groups includestraight and branched chain alkyl groups and cyclic alkyl groups having1 to 12 carbon atoms.

As used herein “loweralkyl” includes both substituted or unsubstitutedstraight or branched chain alkyl groups having from 1 to 6 carbon atoms.Representative loweralkyl groups include, for example, methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, neopentyl, trifluoromethyl,pentafluoroethyl and the like. Loweralkyl groups may be substituted,such as with halo, hydroxy, amino, nitro and/or cyano groups, and thelike. Representative of halo-substituted and hydroxy-substitutedloweralkyl include chloromethyl, trichloromethyl, chloroethyl,hydroxyethyl, and the like. Other suitable substituted loweralkylmoieties include, for example, aralkyl, aminoalkyl, aminoaralkyl,carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,aralkylcarbonylaminoalkyl, aminoalkoxyalkyl and arylaminoalkyl.

“Loweralkoxy” as used herein refers to RO— wherein R is loweralkyl.Representative examples of loweralkoxy groups include methoxy, ethoxy,t-butoxy, trifluoromethoxy and the like.

As used herein, the term “halogen” or “halo” refers to chloro, bromo,fluoro and iodo groups. “Haloalkyl” refers to an alkyl radicalsubstituted with one or more halogen atoms. The term “haloloweralkyl”refers to a loweralkyl radical substituted with one or more halogenatoms. The term “haloalkoxy” refers to an alkoxy radical substitutedwith one or more halogen atoms. The term “haloloweralkoxy” refers to aloweralkoxy radical substituted with one or more halogen atoms.

“Amino” refers herein to the group —NH₂. The term “alkylamino” refersherein to the group —NRR′ where R and R′ are each independently selectedfrom hydrogen or a lower alkyl. The term “arylamino” refers herein tothe group —NRR′ where R is aryl and R′ is hydrogen, a lower alkyl, or anaryl. The term “aralkylamino” refers herein to the group —NRR′ where Ris a lower aralkyl and R′ is hydrogen, a loweralkyl, an aryl, or aloweraralkyl.

The term “alkoxyalkyl” refers to the group -alk₁-O-alk₂ where alk₁ isalkyl or alkenyl, and alk₂ is alkyl or alkenyl. The term“loweralkoxyalkyl” refers to an alkoxyalkyl where alk₁ is loweralkyl orloweralkenyl, and alk₂ is loweralkyl or loweralkenyl. The term“aryloxyalkyl” refers to the group -alkyl-O-aryl. The term“aralkoxyalkyl” refers to the group -alkylenyl-O-aralkyl, where aralkylis a loweraralkyl.

The term “alkoxyalkylamino” refers herein to the group—NR-(alkoxyalkyl), where R is typically hydrogen, loweraralkyl, orloweralkyl. The term “aminoloweralkoxyalkyl” refers herein to anaminoalkoxyalkyl in which the alkoxyalkyl is a loweralkoxyalkyl.

The term “aminocarbonyl” refers herein to the group —C(O)—NH₂.“Substituted aminocarbonyl” refers herein to the group —C(O)—NRR′ whereR is loweralkyl and R′ is hydrogen or a loweralkyl. The term“arylaminocarbonyl” refers herein to the group —C(O)—NRR′ where R is anaryl and R′ is hydrogen, loweralkyl or aryl. “aralkylaminocarbonyl”refers herein to the group —C(O)—NRR′ where R is loweraralkyl and R′ ishydrogen, loweralkyl, aryl, or loweraralkyl.

“Aminosulfonyl” refers herein to the group —S(O)₂—NH₂. “Substitutedaminosulfonyl” refers herein to the group —S(O)₂—NRR′ where R isloweralkyl and R′ is hydrogen or a loweralkyl. The term“aralkylaminosulfonlyaryl” refers herein to the grouparyl-S(O)₂—NH-aralkyl, where the aralkyl is loweraralkyl.

“Carbonyl” refers to the divalent group —C(O)—.

“Carbonyloxy” refers generally to the group —C(O)—O. Such groups includeesters, —C(O)—O—R, where R is loweralkyl, cycloalkyl, aryl, orloweraralkyl. The term “carbonyloxycycloalkyl” refers generally hereinto both an “carbonyloxycarbocycloalkyl” and an“carbonyloxyheterocycloalkyl”, i.e., where R is a carbocycloalkyl orheterocycloalkyl, respectively. The term “arylcarbonyloxy” refers hereinto the group —C(O)—O-aryl, where aryl is a mono- or polycyclic,carbocycloaryl or heterocycloaryl. The term “aralkylcarbonyloxy” refersherein to the group —C(O)—O-aralkyl, where the aralkyl is loweraralkyl.

The term “sulfonyl” refers herein to the group —SO₂—. “Alkylsulfonyl”refers to a substituted sulfonyl of the structure —SO₂R— in which R isalkyl. Alkylsulfonyl groups employed in compounds of the presentinvention are typically loweralkylsulfonyl groups having from 1 to 6carbon atoms in its backbone structure. Thus, typical alkylsulfonylgroups employed in compounds of the present invention include, forexample, methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e.,where R is ethyl), propylsulfonyl (i.e., where R is propyl), and thelike. The term “arylsulfonyl” refers herein to the group —SO₂-aryl. Theterm “aralkylsulfonyl” refers herein to the group —SO₂-aralkyl, in whichthe aralkyl is loweraralkyl. The term “sulfonamido” refers herein to—SO₂NH₂.

As used herein, the term “carbonylamino” refers to the divalent group—NH—C(O)— in which the hydrogen atom of the amide nitrogen of thecarbonylamino group can be replaced a loweralkyl, aryl, or loweraralkylgroup. Such groups include moieties such as carbamate esters(—NH—C(O)—O—R) and amides —NH—C(O)—O—R, where R is a straight orbranched chain loweralkyl, cycloalkyl, or aryl or loweraralkyl. The term“loweralkylcarbonylamino” refers to alkylcarbonylamino where R is aloweralkyl having from 1 to about 6 carbon atoms in its backbonestructure. The term “arylcarbonylamino” refers to group —NH—C(O)—R whereR is an aryl. Similarly, the term “aralkylcarbonylamino” refers tocarbonylamino where R is a lower aralkyl. As used herein, the term“aminocarbonyl” refers to the divalent group —C(O)—NH— in which thehydrogen atom of the amide nitrogen of the carbonylamino group can bereplaced a loweralkyl, aryl, or loweraralkyl group, as described above.

As used herein, the term “guanidino” or “guanidyl” refers to moietiesderived from guanidine, H₂N—C(═NH)—NH₂. Such moieties include thosebonded at the nitrogen atom carrying the formal double bond (the“2”-position of the guanidine, e.g., diaminomethyleneamino, (H₂N)₂C═NH—)and those bonded at either of the nitrogen atoms carrying a formalsingle bond (the “1-” and/or “3”-positions of the guandine, e.g.,H₂N—C(═NH)—NH—). The hydrogen atoms at any of the nitrogens can bereplaced with a suitable substituent, such as loweralkyl, aryl, orloweraralkyl.

As used herein, the term “amidino” refers to the moieties R—C(═N)—NR′—(the radical being at the “N¹” nitrogen) and R(NR′)C═N— (the radicalbeing at the “N²” nitrogen), where R and R′ can be hydrogen, loweralkyl,aryl, or loweraralkyl.

“Cycloalkyl” refers to a mono- or polycyclic, heterocyclic orcarbocyclic alkyl substituent. Typical cycloalkyl substituents have from3 to 8 backbone (i.e., ring) atoms in which each backbone atom is eithercarbon or a heteroatom. The term “heterocycloalkyl” refers herein tocycloalkyl substituents that have from 1 to 5, and more typically from 1to 4 heteroatoms in the ring structure. Suitable heteroatoms employed incompounds of the present invention are nitrogen, oxygen, and sulfur.Representative heterocycloalkyl moieties include, for example,morpholino, piperazinyl, piperadinyl and the like. Carbocycloalkylgroups are cycloalkyl groups in which all ring atoms are carbon. Whenused in connection with cycloalkyl substituents, the term “polycyclic”refers herein to fused and non-fused alkyl cyclic structures.

The term “substituted heterocycle” or “heterocyclic group” orheterocycle as used herein refers to any 3- or 4-membered ringcontaining a heteroatom selected from nitrogen, oxygen, and sulfur or a5- or 6-membered ring containing from one to three heteroatoms selectedfrom the group consisting of nitrogen, oxygen, or sulfur; wherein the5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3double bonds; wherein the nitrogen and sulfur atom maybe optionallyoxidized; wherein the nitrogen and sulfur heteroatoms maybe optionallyquarternized; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another 5- or6-membered heterocyclic ring independently defined above. The term“heterocycle” thus includes rings in which nitrogen is the heteroatom aswell as partially and fully-saturated rings. Preferred heterocyclesinclude, for example: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl,imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, morpholinyl,thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,furyl, thienyl, triazolyl and benzothienyl.

Heterocyclic moieties can be unsubstituted or monosubstituted ordisubstituted with various substituents independently selected fromhydroxy, halo, oxo (C═O), alkylimino (RN═, wherein R is a loweralkyl orloweralkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl,alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl.

The heterocyclic groups may be attached at various positions as will beapparent to those having skill in the organic and medicinal chemistryarts in conjunction with the disclosure herein.

where R is H or a heterocyclic substituent, as described herein.

Representative heterocyclics include, for example, imidazolyl, pyridyl,piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl,benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, indolyl, naphthpyridinyl, indazolyl, andquinolizinyl.

“Aryl” refers to optionally substituted monocyclic and polycyclicaromatic groups having from 3 to 14 backbone carbon or hetero atoms, andincludes both carbocyclic aryl groups and heterocyclic aryl groups.Carbocyclic aryl groups are aryl groups in which all ring atoms in thearomatic ring are carbon. The term “heteroaryl” refers herein to arylgroups having from 1 to 4 heteroatoms as ring atoms in an aromatic ringwith the remainder of the ring atoms being carbon atoms. When used inconnection with aryl substituents, the term “polycyclic aryl” refersherein to fused and non-fused cyclic structures in which at least onecyclic structure is aromatic, such as, for example, benzodioxozolo(which has a heterocyclic structure fused to a phenyl group, i.e.,

naphthyl, and the like. Exemplary aryl moieties employed as substituentsin compounds of the present invention include phenyl, pyridyl,pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl,pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl,naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and thelike.

“Aralkyl” refers to an alkyl group substituted with an aryl group.Typically, aralkyl groups employed in compounds of the present inventionhave from 1 to 6 carbon atoms incorporated within the alkyl portion ofthe aralkyl group. Suitable aralkyl groups employed in compounds of thepresent invention include, for example, benzyl, picolyl, and the like.

Representative heteroaryl groups include, for example, those shownbelow. These heteroaryl groups can be further substituted and may beattached at various positions as will be apparent to those having skillin the organic and medicinal chemistry arts in conjunction with thedisclosure herein.

Representative heteroaryl's include, for example, imidazolyl, pyridyl,piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl,benzothiazolyl, and benzoxazolyl.

The term “biaryl” refers to a group or substituent to which two arylgroups, which are not condensed to each other, are bound. Exemplarybiaryl compounds include, for example, phenylbenzene, diphenyldiazene,4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene,diphenyl ketone, (4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine,(phenylmethoxy)benzene, and the like. Preferred optionally substitutedbiaryl groups include:2-(phenylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide,1,4-diphenylbenzene,N-[4-(2-phenylethynyl)phenyl]-2-[benzyl-amino]acetamide,2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide,2-amino-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(cyclopropylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide,2-(ethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-[(2-methylpropyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,5-phenyl-2H-benzo-[d]1,3-dioxolene, 2-chloro-1-methoxy-4-phenylbenzene,2-[(imidazolylmethyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,4-phenyl-1-phenoxybenzene,N-(2-aminoethyl)-[4-(2-phenylethynyl)phenyl]carboxamide,2-{[(4-fluorophenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,2-{[(4-methylphenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,4-phenyl-1-(trifluoromethyl)benzene, 1-butyl-4-phenylbenzene,2-(cyclohexylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(ethylmethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(butylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(quinuclidin-3-ylamino)acetamide,N-[4-(2-phenylethynyl)phenyl]pyrrolidin-2-ylcarboxamide,2-amino-3-methyl-N-[4-(2-phenylethynyl)-phenyl]butanamide,4-(4-phenylbuta-1,3-diynyl)phenylamine,2-(dimethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,2-(ethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,4-ethyl-1-phenylbenzene, 1-[4-(2-phenylethynyl)phenyl]ethan-1-one,N-(1-carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta-1,3-diynyl)phenyl]carboxamide,N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxyphenyl phenyl ketone,phenyl-N-benzamide, (tert-butoxy)-N-[(4-phenylphenyl)methyl]carboxamide,2-(3-phenylphenoxy)ethanehydroxamic acid, 3-phenylphenyl propanoate,1-(4-ethoxyphenyl)-4-methoxybenzene, and[4-(2-phenylethynyl)phenyl]pyrrole.

The term “heteroarylaryl” refers to a biaryl group where one of the arylgroups is a heteroaryl group. Exemplary heteroarylaryl groups include,for example, 2-phenylpyridine, phenylpyrrole,3-(2-phenylethynyl)pyridine, phenylpyrazole,5-(2-phenylethynyl)-1,3-dihydropyrimidine-2,4-dione,4-phenyl-1,2,3-thiadiazole, 2-(2-phenylethynyl)pyrazine,2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)-furan,3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferredoptionally substituted heteroarylaryl groups include:5-(2-phenylethynyl)pyrimidine-2-ylamine, 1-methoxy-4-(2-thienyl)benzene,1-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenylpyridine,5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl)phenyl]furan,3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene,(hydroxyimino)(5-phenyl(2-thienyl))methane,5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene,2-(4-ethylphenyl)thiophene, 4-methylthio-1-(2-thienyl)benzene,2-(3-nitrophenyl)thiophene,(tert-butoxy)-N-[(5-phenyl(3-pyridyl))methyl]carboxamide,hydroxy-N-[(5-phenyl(3-pyridyl))methyl]-amide,2-(phenylmethylthio)pyridine, and benzylimidazole.

The term “heteroarylheteroaryl” refers to a biaryl group where both ofthe aryl groups is a heteroaryl group. Exemplary heteroarylheteroarylgroups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine,and the like. Preferred optionally substituted heteroarylheteroarylgroups include: 2-(4-piperazinyl-3-pyridyl)furan,diethyl(3-pyrazin-2-yl(4-pyridyl))amine, and dimethyl{2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl)}amine.

“Optionally substituted” or “substituted” refers to the replacement ofhydrogen with a monovalent or divalent radical. Suitable substitutiongroups include, for example, hydroxyl, nitro, amino, imino, cyano, halo,thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl,loweralkyl, haloloweralkyl, loweralkyamino, haloloweralkylamino,loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl,aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl,heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and thelike.

The substitution group can itself be substituted. The group substitutedonto the substitution group can be carboxyl, halo; nitro, amino, cyano,hydroxyl, loweralkyl, loweralkoxy, aminocarbonyl, —SR, thioamido, —SO₃H,—SO₂R or cycloalkyl, where R is typically hydrogen, hydroxyl orloweralkyl.

When the substituted substituent includes a straight chain group, thesubstitution can occur either within the chain (e.g., 2-hydroxypropyl,2-aminobutyl, and the like) or at the chain terminus (e.g.,2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substitutentscan be straight chain, branched or cyclic arrangements of covalentlybonded carbon or heteroatoms.

As used herein, the term “carboxy-protecting group” refers to a carbonylgroup which has been esterified with one of the commonly used carboxylicacid protecting ester groups employed to block or protect the carboxylicacid function while reactions involving other functional sites of thecompound are carried out. In addition, a carboxy protecting group can beattached to a solid support whereby the compound remains connected tothe solid support as the carboxylate until cleaved by hydrolytic methodsto release the corresponding free acid. Representativecarboxy-protecting groups include, for example, loweralkyl esters,secondary amides and the like.

As used herein, the term “pharmaceutically acceptable salts” refers tothe nontoxic acid or alkaline earth metal salts of the compounds ofFormula I. These salts can be prepared in situ during the finalisolation and purification of the compounds of Formula I, or byseparately reacting the base or acid functions with a suitable organicor inorganic acid or base, respectively. Representative salts includebut are not limited to the following: acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containinggroups can be quaternized with such agents as loweralkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides, and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides, and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of formula (I), orseparately by reacting carboxylic acid moieties with a suitable basesuch as the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation or with ammonia, or an organic primary,secondary or tertiary amine. Pharmaceutically acceptable salts include,but are not limited to, cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, calcium, magnesium, aluminumsalts and the like, as well as nontoxic ammonium, quaternary ammonium,and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters, which hydrolyze in vivo and include those that break downreadily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “cancer” refers to cancer diseases that can be beneficiallytreated by the inhibition of Raf kinase, including, for example, solidcancers, such as carcinomas (e.g., of the lungs, pancreas, thyroid,bladder or colon), myeloid disorders (e.g., myeloid leukemia) andadenomas (e.g., villous colon adenoma).

In illustrative embodiments of the invention, Ar₁ may be, for example,phenyl which may be substituted by one or more substitutents selectedfrom the group consisting of hydroxyl, nitro, cyano, halo, andsubstituted or unsubstituted amino, imino, thio, sulfonyl, thioamido,amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino,sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl,loweralkyamino, haloloweralkylamino, loweralkoxy, haloloweralkoxy,loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl,heterocycloalkylloweralkylaminocarbonyl,carboxylloweralkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like. In other illustrative embodiments of theinvention, Ar₂ may be, for example, pyridyl, which may be substituted byone or more substitutents selected from the group consisting ofhydroxyl, nitro, cyano, halo, and substituted or unsubstituted amino,imino, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,methoxamidino, imidino, guauidino, sulfonamido, carboxyl, formyl,loweralkyl, haloloweralkyl, loweralkyamino, haloloweralkylamino,loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl,aminocarbonyl, loweralkylaminocarbonyl,heterocycloalkylloweralkylaminocarbonyl,carboxylloweralkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like.

In representative embodiments of the invention, the compounds of theinvention include, for example,4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,4-({2-[(3-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(3-chloro-4-fluorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-{[2-(phenylamino)-1H-benzimidazol-6-yl]oxy}pyridine-2-carboxamide,4-[(2-{[4-bromo-2-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2-methylpropyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-[(2-{[4-(dimethylamino)naphthalen-1-yl]-amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(4-nitrophenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,N-methyl-4-({2-[(phenylcarbonyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,N-methyl-4-({2-[(phenylmethyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,methyl4-{[6-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}benzoate,4-({2-[(4-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-[(2-{[2-(ethyloxy)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2-morpholin-4-ylethyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-({2-[(4-iodophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]pyridine-2-carboxamide,4-({2-[(furan-2-ylmethyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-bromo-3-methylphenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-acetylphenyl)amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2,4,6-trimethylphenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-[(2-{[4-(1,1-dimethylethyl)-phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,4-({2-[(2-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(3-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(2-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,methyl3-{[6-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}thiophene-2-carboxylate,4-({2-[(4-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]pyrrolidin-3-yl}pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide,4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N-dimethylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide,N-(4-bromophenyl)-1-methyl-5-{[2-(pyrrolidin-1-ylcarbonyl)pyridin-4-yl]oxy)}-1H-benzimidazol-2-amine,ethyl(3R)-3-(methyloxy)-4-[({4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-carbonyl)amino]piperidine-1-carboxylate,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)ethyl]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(tetrahydrofuran-2-ylmethyl)pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(piperidin-4-ylmethyl)pyridine-2-carboxamide,5-({2-[(3-aminopyrrolidin-1-yl)carbonyl]pyridin-4-yl}oxy)-N-(4-bromophenyl)-1-methyl-1H-benzimidazol-2-amine,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[1-(diphenylmethyl)azetidin-3-yl]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-piperidin-3-ylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,3-thiazol-2-yl)pyridine-2-carboxamide,and4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-2-carboxamide,(4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide,(4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide,and other representative compounds set forth in the Examples.

In other aspects, the present invention relates to the processes forpreparing the compounds of Formulas I, II, III, IV and V and to thesynthetic intermediates useful in such processes.

The compounds of the invention comprise asymmetrically substitutedcarbon atoms. Such asymmetrically substituted carbon atoms can result inthe compounds of the invention comprising mixtures of stereoisomers at aparticular asymmetrically substituted carbon atom or a singlestereoisomer. As a result, racemic mixtures, mixtures of diastereomers,as well as single diastereomers of the compounds of the invention areincluded in the present invention. The terms “S” and “R” configuration,as used herein, are as defined by the IUPAC 1974 RECOMMENDATIONS FORSECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Appl. Chem. 45:13-30(1976). The terms α and β are employed for ring positions of cycliccompounds. The α-side of the reference plane is that side on which thepreferred substituent lies at the lower numbered position. Thosesubstituents lying on the opposite side of the reference plane areassigned β descriptor. It should be noted that this usage differs fromthat for cyclic stereoparents, in which “α” means “below the plane” anddenotes absolute configuration. The terms α and β configuration, as usedherein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE-APPENDIX IV(1987) paragraph 203.

The present invention also relates to the processes for preparing thecompounds of the invention and to the synthetic intermediates useful insuch processes, as described in detail below.

Synthetic Methods

Compounds of the invention containing a benzimidazole core may beprepared using a number of methods familiar to one of skill in the art.In one method, suitably functionalized diamines may be coupled withvarious thioisocyanates to form the intermediate thioureas. Cyclizationto form the benzimidazole moiety may be effected under known conditionssuch as with treatment carbodiimides or alkyl halides as in thefollowing schemes.

Scheme:

Scheme:

Alternatively the diamines may be reacted sequentially with carbonyldiimidazole and phosphoryl chloride followed by coupling with theappropriate amine.

Compounds containing the oxazole structure may similarly be preparedaccording to the methods above or according to other known generalprocedures. Haviv et al. (J. Med. Chem. 1988, 31:1719) describes aprocedure for assembling oxazole cores wherein a hydroxy aniline istreated with ethyl potassium xanthate. The resulting sulfurylbenzoxazole may then be chlorinated and coupled with an amine.

Compounds containing a benzothiazole core may also be prepared accordingto known methods. An ortho-halothioisocyanate may be reacted with anamine to form a thiourea. Reduction with NaH then allows formation ofthe thiazole ring.

Benzothiazoles may generally be substituted in accordance with thepresent invention, such as through the following synthetic pathway:

Benzoxzoles may generally be synthesized through the following pathway:

The compounds of the invention are useful in vitro or in vivo ininhibiting the growth of cancer cells. The compounds may be used aloneor in compositions together with a pharmaceutically acceptable carrieror excipient. Suitable pharmaceutically acceptable carriers orexcipients include, for example, processing agents and drug deliverymodifiers and enhancers, such as, for example, calcium phosphate,magnesium stearate, talc, monosaccharides, disaccharides, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, lowmelting waxes, ion exchange resins, and the like, as well ascombinations of any two or more thereof. Other suitable pharmaceuticallyacceptable excipients are described in “Remington's PharmaceuticalSciences,” Mack Pub. Co., New Jersey (1991), incorporated herein byreference.

Effective amounts of the compounds of the invention generally includeany amount sufficient to detectably inhibit Raf activity by any of theassays described herein, by other Raf kinase activity assays known tothose having ordinary skill in the art or by detecting an inhibition oralleviation of symptoms of cancer.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy. The therapeutically effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

For purposes of the present invention, a therapeutically effective dosewill generally be a total daily dose administered to a host in single ordivided doses may be in amounts, for example, of from 0.001 to 1000mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg bodyweight daily. Dosage unit compositions may contain such amounts ofsubmultiples thereof to make up the daily dose.

The compounds of the present invention may be administered orally,parenterally, sublingually, by aerosolization or inhalation spray,rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches orionophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordi-glycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols, which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33 et seq. (1976).

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents used in the treatment of cancer. Representativeagents useful in combination with the compounds of the invention for thetreatment of cancer include, for example, irinotecan, topotecan,gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec),anthracyclines, rituximab, trastuzumab, as well as other cancerchemotherapeutic agents.

The above compounds to be employed in combination with the compounds ofthe invention will be used in therapeutic amounts as indicated in thePhysicians' Desk Reference (PDR) 47th Edition (1993), which isincorporated herein by reference, or such therapeutically useful amountsas would be known to one of ordinary skill in the art.

The compounds of the invention and the other anticancer agents can beadministered at the recommended maximum clinical dosage or at lowerdoses. Dosage levels of the active compounds in the compositions of theinvention may be varied so as to obtain a desired therapeutic responsedepending on the route of administration, severity of the disease andthe response of the patient. The combination can be administered asseparate compositions or as a single dosage form containing both agents.When administered as a combination, the therapeutic agents can beformulated as separate compositions, which are given at the same time ordifferent times, or the therapeutic agents, can be given as a singlecomposition.

Antiestrogens, such as tamoxifen, inhibit breast cancer growth throughinduction of cell cycle arrest, that requires the action of the cellcycle inhibitor p27Kip. Recently, it has been shown that activation ofthe Ras-Raf-MAP Kinase pathway alters the phosphorylation status ofp27Kip such that its inhibitory activity in arresting the cell cycle isattenuated, thereby contributing to antiestrogen resistance (Donovan etal, J. Biol. Chem. 276:40888, 2001). As reported by Donovan et al.,inhibition of MAPK signaling through treatment with MEK inhibitorchanged the phosphorylation status of p27 in hormone refractory breastcancer cell lines and in so doing restored hormone sensitivity.Accordingly, in one aspect, the compounds of formulas (I), (II), (III),(IV) and (V) may be used in the treatment of hormone dependent cancers,such as breast and prostate cancers, to reverse hormone resistancecommonly seen in these cancers with conventional anticancer agents.

In hematological cancers, such as chronic myelogenous leukemia (CML),chromosomal translocation is responsible for the constitutivelyactivated BCR-AB1 tyrosine kinase. The afflicted patients are responsiveto Geevec, a small molecule tyrosine kinase inhibitor, as a result ofinhibition of Ab1 kinase activity. However, many patients with advancedstage disease respond to Gleevec initially, but then relapse later dueto resistance-conferring mutations in the Ab1 kinase domain. In vitrostudies have demonstrated that BCR-Av1 employs the Raf kinase pathway toelicit its effects. In addition, inhibiting more than one kinase in thesame pathway provides additional protection againstresistance-conferring mutations. Accordingly, in another aspect of theinvention, the compounds of formulas (I), (II), (III), (IV) and (V) areused in combination with at least one additional agent, such as Gleevec,in the treatment of hematological cancers, such as chronic myelogenousleukemia (CML), to reverse or prevent resistance to the at least oneadditional agent.

The present invention will be understood more readily by reference tothe following examples, which are provided by way of illustration andare not intended to be limiting of the present invention.

Representative side chains for use in the compounds of the followingexamples may generally be prepared in accordance with the followingprocedures:

Example 1 Synthesis of4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide

The compound4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamidewas synthesized as follows:

Step 1. Synthesis of4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide

A mixture containing 4-amino-3-nitrophenol (1 eq) and potassiumbis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2hours at room temperature. To this mixture was added(4-chloro(2-pyridyl))-N-methylcarboxamide (1 eq) and potassium carbonate(1.2 eq) and stirred at 90° C. for 3 days. The reaction mixture was thenconcentrated and partitioned between ethyl acetate and water. Theorganic layer was separated and washed with brine, dried, filtered, andconcentrated in vacuum to give brown solid. Purification on silica gel(2% triethyl amine/50% ethyl acetate in hexane) gave4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide as anorange solid. The product gave satisfactory NMR. HPLC, 3.39 min; MS:MH+=289.

Step 2. Synthesis of4-[(3,4-diaminophenyl)oxy]-N-methylpyridine-2-carboxamide

The mixture containing [4-(3-amino-4-nitrophenoxy)(2-pyridyl)]-N— inmethanol with catalytic amount of 10% Pd/C was hydrogenated untildisappearance of the yellow color to yield the product amine. HPLC, 2.5mins; MS: MH+=259.

Step 3. Synthesis of4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide

The mixture containing4-[(3,4-diaminophenyl)oxy]-N-methylpyridine-2-carboxamide (1 eq) and4-chloro-3-(trifluoromethyl)benzeneisothiocyanate (1 eq) intetrahydrofuran was stirred at room temperature for 16 hours to give thecorresponding thiourea. To the resulting mixture was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq) andthe mixture was stirred for another 10 hours. The mixture wasconcentrated and partitioned between ethyl acetate and water. Theorganic layer was washed with brine and dried. Purification on HPLC gave4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide.MS: MH+=462

Examples 2-108

The compounds shown in the following Table 1 (Examples 2-108) wereprepared from following the procedure described for Example 1.

TABLE 1 Example Structure Name MH+ 2

4-({2-[(3-chlorophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 394 3

4-({2-[(4-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 440 4

4-({2-[(3-chloro-4-fluorophenyl)- amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2-carbox- amide 412 5

N-methyl-4-{[2-(phenylamino)- 1H-benzimidazol-6-yl]oxy}-pyridine-2-carboxamide 360 6

4-[(2-{[4-bromo-2-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl- pyridine-2-carboxamide 508 7

N-methyl-4-({2-[(2-methylpropyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 340 8

4-[(2-{[4-(dimethylamino)- naphthalen-1-yl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl- pyridine-2-carboxamide 453 9

N-methyl-4-({2-[(4-nitrophenyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 405 10

N-methyl-4-({2-[(phenylcarbonyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 388 11

N-methyl-4-({2-[(phenylmethyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 374 12

methyl 4-{[6-({2-[(methylamino)- carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}benzoate 418 13

4-({2-[(4-chlorophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 394 14

4-[(2-{[2-(ethyloxy)phenyl]- amino}-1H-benzimidazol-6-yl)-oxy]-N-methylpyridine-2- carboxamide 404 15

N-methyl-4-({2-[(2-morpholin-4- ylethyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide 397 16

4-({2-[(4-iodophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 486 17

N-methyl-4-[(2-{[4-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]pyridine-2- carboxamide 428 18

4-({2-[(furan-2-ylmethyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 364 19

4-({2-[(4-bromo-3-methylphenyl)- amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2- carboxamide 453 20

4-({2-[(4-acetylphenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 402 21

N-methyl-4-({2-[(2,4,6-trimethyl- phenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide 402 22

4-[(2-{[4-(1,1-dimethylethyl)- phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2- carboxamide 416 23

4-({2-[(2-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 440 24

4-({2-[(3-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 440 25

4-({2-[(2-chlorophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 394 26

methyl 3-{[6-({2-[(methylamino)- carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}- thiophene-2-carboxylate 424 27

4-({2-[(4-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]- pyrrolidin-3-yl}pyridine-2- carboxamide539 28

(4-{2-[(2,5-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.3 29

(4-{2-[(2,4-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.3 30

N-methyl[4-(2-{[2-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- carboxamide 427.3 31

(4-{2-[(3,4-dichlorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 428.2 32

N-methyl(4-{2-[(2-methylthio- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 405.4 33

N-methyl(4-{2-[(4-methylthio- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 405.4 34

(4-{2-[(2-methoxyphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 389.4 35

(4-{2-[(2-fluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 377.3 36

N-methyl(4-{2-[(4-sulfamoyl- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 438.4 37

N-methyl[4-(2-{[2-(trifluoro- methoxy)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- carboxamide 443.3 38

(4-{2-[(3,4-dimethoxyphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 419.4 39

[4-(2-{[2-fluoro-5-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- N-methylcarboxamide 445.3 40

(4-{2-[(2,4-dichlorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 428.2 41

N-methyl[4-(2-{[3-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- carboxamide 427.3 42

(4-{2-[(3-methoxyphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 389.4 43

N-methyl(4-{2-[(2-phenylphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 435.4 44

[4-(2-{[2-chloro-5-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- N-methylcarboxamide 461.8 45

(4-{2-[(2,5-dimethoxyphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 419.4 46

(4-{2-[(3,5-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.3 47

(4-{2-[(2-ethylphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 387.4 48

(4-{2-[(3,5-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.4 49

[4-(2-{[3,5-bis(trifluoromethyl)- phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]-N-methyl- carboxamide 495.4 50

(4-{2-[(2-methoxy-5- methylphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 403.4 51

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-6-yloxy}(2-pyridyl))-N-methylcarboxamide 452.3 52

N-methyl[4-(2-{[2-(methylethyl)- phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]carboxamide 401.4 53

(4-{2-[(2-methoxy-4-nitrophenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 434.4 54

(4-{2-[(3,5-dimethoxyphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 420.1 55

(4-{2-[(5-chloro-2,4-dimethoxy- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 454.1 56

N-methyl-4-[(2-{[2-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 402.5 57

N-methyl-4-[(2-{[2-(methyloxy)-4- nitrophenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 435.4 58

4-({2-[(4-ethylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 388.4 59

4-[(2-{[3,5-bis(methyloxy)phenyl]- amino}-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2- carboxamide 420.4 60

4-[(2-{[5-chloro-2,4-bis(methyl- oxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 454.9 61

4-({2-[(4-cyclohexylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 442.5 62

4-({2-[(3,4-difluorophenyl)amino]- 1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 396.4 63

4-({2-[(3,4-dimethylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 388.4 64

4-({2-[(4-bromo-3-chlorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 473.7 65

4-({2-[(4-butylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 416.5 66

N-methyl-4-[(2-{[4-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 402.5 67

4-({2-[(2,6-dichlorophenyl)amino]- 1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 429.3 68

N-methyl-4-[(2-{[4-(phenyloxy)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 452.5 69

4-({2-[(3,5-dimethylphenyl)- amino]-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 388.4 70

4-[(2-{[4-(diethylamino)phenyl]- amino}-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2- carboxamide 431.5 71

4-({2-[(4-chloro-2-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 72

4-({2-[(4-bromo-2-chlorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 473.7 73

4-[(2-{[2-bromo-4-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 481.4 74

4-({2-[(2-chloro-4-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 75

4-({2-[(2-bromo-4-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 453.3 76

4-[(2-{[2-chloro-4-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 462.8 77

4-({2-[(4-chloro-2-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 78

4-{[2-(2,3-dihydro-1H-inden-5- ylamino)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 400.5 79

4-({2-[(2,5-dimethylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 388.4 80

4-({2-[(4-fluoro-2-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 392.4 81

N-methyl-4-({2-[(2,3,5-trifluoro- phenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 414.4 82

4-({2-[(2-chloro-5-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 83

4-({2-[(4-bromo-3-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 457.3 84

4-[(2-{[3-(1,1-dimethylethyl)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 416.5 85

4-({2-[(2,4-dibromophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 518.2 86

4-({2-[(3-chloro-4-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 87

4-[(2-{[4-bromo-2-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 507.3 88

4-({2-[(2,5-dichlorophenyl)amino]- 1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 429.3 89

N-methyl-4-{[2-({4-[(trifluoro- methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine- 2-carboxamide 444.4 90

4-{[2-(1,3-benzodioxol-5-yl- amino)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 404.4 91

4-({2-[(3-chloro-4-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 92

4-({2-[(4-chloro-3-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 93

4-[(2-{[3-chloro-4-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 462.8 94

4-[(2-{[4-fluoro-3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 446.4 95

4-({2-[(4-chloro-3-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 96

4-{[2-({4-bromo-2-[(trifluoro- methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 523.3 97

N-methyl-4-[(2-{[3-(methylthio)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 406.5 98

N-methyl-4-[(2-{[4-(methyloxy)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 390.4 99

4-({2-[(3-ethylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 388.4 100

N-methyl-4-{[2-({4-[(trifluoro- methyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 460.4 101

4-({2-[(4-fluorophenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 378.4 102

N-methyl-4-{[2-({3-[(trifluoro- methyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 460.4 103

N-methyl-4-[(2-{[4-methyl-3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 442.4 104

4-({2-[(4-bromo-2-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 457.3 105

4-[(2-{[5-chloro-2-(methyloxy)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 424.9 106

N-methyl-4-[(2-{[4-(methyloxy)- 1,1′-biphenyl-3-yl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 466.5 107

4-({2-[(3-fluorophenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 378.4 108

4-{[2-({3-bromo-4-[(trifluoro- methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 523.3

Example 109 Synthesis of(4-{2-[(4-bromophenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamideStep 1. Synthesis of 2-bromo-5-methoxybenzothiazole

A solution of bromine (3.6 eq) in chloroform (0.75M) was added dropwiseover a period of 1 hr to a stirred suspension of5-methoxy-2-mercaptobenzothiazole (1 eq) in chloroform at 0° C. Themixture was stirred for 30 min before it was added slowly to water andstirred for further 20 min. The mixture was filtered to remove a creamsolid. The organic phase was dried and evaporated to leave a brownsolid. The brown solid was dissolved in ether and filtered. The residuewas washed with ether and the filtrate and washings were combined andevaporated, chromatographed (4:1 hexanes and ethyl acetate) to give thetitle compound as a pale yellow solid. MS: MH⁺=244

Step 2. Synthesis of (4-bromophenyl)(5-methoxybenzothiazol-2-yl)amine

The mixture containing 2-bromo-5-methoxybenzthiazole (1 eq),4-Bromoaniline (2 eq) and disopropylethylamine was subjected tomicrowave in NMP at 220° C. The resultant mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried. Purification on silica gel gave the desiredproduct. MS: MH⁺=335

Step 3. Synthesis of 2-[(4-bromophenyl)amino]benzothiazol-5-ol

The mixture of (4-bromophenyl)(5-methoxybenzothiazol-2-yl)amine andhydrobromic acid (48%) was subjected to the microwave at 150° C. for 6mins to yield the desired product. MS: MH⁺=321

Step 4. Synthesis of(4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide

The mixture containing 2-[(4-bromophenyl)amino]benzothiazol-5-ol (1 eq),Potassiumbis(trimethylsilyl)amide (4 eq), was stirred indimethylformamide for 30 min at room temperature. To this mixture wasadded (4-chloro(2-pyridyl)-N-methylcarboxamide (1 eq) and Potassiumcarbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reactionmixture was then concentrated and partitioned between ethyl acetate andwater. The organic layer was separated and washed with brine, dried,filtered and concentrated. Purification on Prep LC yielded the desiredproduct. MS: MH⁺=455

Each of the Examples 110-119 shown in the following Table 2 weresynthesized according to the procedure described in Example 109:

TABLE 2 Example Structure Name MH+ 110

(4-{2-[(4-bromophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 455 111

(4-{2-[(4-chlorophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 411.1 112

N-methyl(4-{2-[(4-methylphenyl)- amino]benzothiazol-5-yloxy}(2-pyridyl))carboxamide 391.1 113

N-methyl[4-(2-{[4-(trifluoro- methoxy)phenyl]amino}-benzothiazol-5-yloxy)(2-pyridyl)]- carboxamide 461.1 114

(4-{2-[(4-butylphenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 433.2 115

N-methyl[4-(2-{[4-(methylethyl)- phenyl]amino}benzothiazol-5-yloxy)(2-pyridyl)]carboxamide 419.2 116

(4-{2-[(3,4-dichlorophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 445 117

(4-{2-[(4-bromophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-(2-morpholin-4-ylethyl)- carboxamide 554.1 118

N-((3R)pyrrolidin-3-yl)(4-{2-[(4- bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))carboxamide 510 119

N-[(3R,5R)-5-(methoxymethyl)- pyrrolidin-3-yl](4-{2-[(4-bromo-phenyl)amino]benzothiazol 554.1

Example 120a Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

The compound4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamidewas synthesized as follows:

Step 1. Synthesis of4-{[3-amino-4-(methylamino)phenyl]oxy}-N-methylpyridine-2-carboxamide

A solution of4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide (1 eq) inmethylene chloride was treated with trifluoroacetic anhydride (1 eq) andstirred for 10 minutes at 0° C. The mixture was quenched with saturatedNaHCO3 solution. The organic layer was separated and washed with water,brine, dried and evaporated. MS: MH+=385.2.

To a solution of the trifluoroacetamide (1 eq) in a mixture of toluene,acetonitrile and sodium hydroxide solution (50%) was addedbenzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq).The biphasic mixture was stirred overnight at room temperature andevaporated. The mixture was taken up in ethyl acetate, washed withwater, brine, dried and evaporated. The crude product was purified bycolumn chromatography eluting with 1:1 hexanes and ethylacetate followedby 2% triethylamine in 1:1 hexanes and ethyl acetate followed by 2%triethylamine in 1:1 hexanes and ethyl acetate to affordN-methyl-4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridine-2-carboxamide asa reddish orange solid. MS: MH+=303.1.

The solution of nitromethylaniline in methanol was treated with 5%palladium on carbon and stirred under hydrogen atmosphere for 15 min.(until the disappearance of yellow coloration) at room temperature. Themixture was filtered and the filtrate was concentrated to provide 0.36 gof the diamine4-{[3-amino-4-(methylamino)phenyl]oxy}-N-methylpyridine-2-carboxamide.MS: MH+=273.3.

Step 2. Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

A solution of the diamine4-{[3-amino-4-(methylamino)phenyl]oxy}-N-methylpyridine-2-carboxamide (1eq) in methanol was treated with 4-bromophenylisothiocyanate (1 eq) andstirred at 60° C.-65° C. for 2 hours. The reaction mixture was cooleddown to room temperature and methyl iodide (1 eq) was added and stirredovernight at 60° C. The reaction was cooled to room temperature,evaporated, taken up in ethyl acetate, and washed with water and brine,dried, and evaporated under reduced pressure. Column chromatographyusing a gradient solvent system of hexanes and ethyl acetate and either1:1 methylene chloride and acetone or 5% methanol in methylene chlorideyielded the product as a half white powder. MS: MH+=452.3

Example 120b Alternative Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamideStep 1. Synthesis ofN-methyl{4-[4-(methylamino)-3-aminophenoxy](2-pyridyl)}carboxamide

A mixture containing 4-amino-3-nitrophenol 5 (1.0 g, 6.4 mmol),potassium bis(trimethylsilyl)amide (2.58 g, 12.8 mmol) was stirred inDMF (50 ml) for 2 hours at rt. To this mixture was added(4-chloro(2-pyridyl))-N-methylcarboxamide 4 (1.09 g, 6.4 mmol) andpotassium carbonate (0.5 g, 7.6 mmol) and stirred at 90° C. overnight.The reaction mixture was then concentrated and partitioned between ethylacetate and water. The organic layer was separated and washed with brine(2×10 ml), dried, filtered and concentrated in vacuum to give brownsolid. Purification on silica gel with 2% triethyl amine in 50% ethylacetate in hexane gave 1.3 g (yield, 72%) of[4-(4-amino-3-nitrophenoxy)(2-pyridyl)]-N-methylcarboxamide 6 as anorange solid: ¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, J=5.6 Hz, 1H), 7.99 (brs, 1H), 7.90 (d, J=2.7 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H), 7.17 (dd, J=2.7,9.0 Hz, 1H), 6.95 (ddd, J=0.7, 2.5, 5.6 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H),6.18 (br s, 2H), 3.00 (d, J=5.1 Hz, 3H); mp 208-210° C. dec; LCMS m/z289.2 (MH⁺), t_(R)=1.92 min.

A 500 mL three neck round bottom flask fitted with a mechanical stirrerwas charged with nitroaniline 6 (10.0 g, 34.8 mmol) and CH₂Cl₂ (175 ml).The resulting suspension was cooled to 0° C. and TFAA (9.5 mL, 14.1 g,67.0 mmol) was added over 16 h while allowing the cooling bath toexpire.² After the reaction was judged complete by TLC,³ TBACl (5.2 g,17.5 mmol)⁴ and dimethyl sulfate (6.7 mL, 8.9 g, 70.0 mmol) were addedfollowed by 50% aqueous NaOH solution (140 mL). The resulting reactionmixture was cooled with an ice bath, and stirred vigorously for 1.5 h atrt.^(3,5,6) The reaction was then poured over ice water and theresulting phases were partitioned and separated. The aqueous phase wasextracted with CH₂Cl₂ (3×100 mL) and the combined organic layers werewashed with brine (2×100 mL), dried (MgSO₄), and concentrated. The cruderesidue was purified by recrystallization (1:3 ethanol-water) to give8.36 g (27.7 mmol, 79%) of 7 as fine red needles: ¹H NMR (300 MHz,CDCl₃) δ 8.40 (dd, J=0.5, 4.9 Hz, 1H), 8.07 (br d, J=3.7 Hz, 1H), 7.98(br s, 1H), 7.95 (d, J=2.9 Hz, 1H), 7.62 (dd, J=0.5, 2.9 Hz, 1H), 7.27(ddd, J=0.5, 2.9, 9.3 Hz, 1H), 6.98 (dd, J=2.7, 5.6 Hz, 1H), 6.92 (d,J=9.3 Hz, 1H), 3.07 (d, J=5.1 MHz, 3H), 3.00 (d, J=5.1 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 166.6, 164.6, 152.6, 150.0, 144.8, 142.2, 130.6,118.9, 115.5, 114.2, 109.7, 30.2, 26.4; mp 164-166° C. LCMS m/z 303.4(MH⁺), t_(R)=2.37 min.

A suspension of nitroaniline 7 (5.0 g, 16.5 mmol) in methanol wassparged with N₂ for 20 min after which 10% Pd/C (0.88 g, 0.8 mmol) wasadded. The reaction was purged with H₂ and maintained under a H₂atmosphere overnight at room temperature. The reaction was purged withN₂ and filtered through Celite. The collected solids were washed withEtOAc (3×50 mL), and the combined organic layers were dried (MgSO₄) andconcentrated to afford 4.35 g (16.0 mmol, 97%) of an off white solid as8: ¹H NMR (300 MHz, CDCl₃) δ 8.30 (d, J=5.5 Hz, 1H), 7.99 (br s, 1H),7.67 (d, J=2.5 Hz, 1H), 6.91 (dd, J=2.5, 5.5 Hz, 1H), 6.62 (d, J=8.5 Hz,1H), 6.53 (dd, J=2.5, 8.5 Hz, 1H), 6.44 (d, J=2.5 Hz, 1H), 2.98 (d,J=5.2 Hz, 3H), 2.86 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.4, 164.9,152.2, 149.6, 146.0, 136.6, 136.3, 114.0, 112.3, 112.0, 110.2, 109.0,31.6, 26.5; mp 153-156° C. dec.; LCMS m/z 273.3 (MH⁺), t_(R)=1.66 min.

Step 2. Synthesis of(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide

A 250 mL round bottom flask was charged with4-bromophenylisothiocyanate¹ (2.17 g, 10.1 mmol), diamine 8 (2.74 g,10.1 mmol), and MeOH (40 mL) and the reaction was maintained at rtovernight. Ferric chloride (2.43 g, 15 mmol) was added and the resultingred reaction mixture was stirred overnight. The reaction was partitionedwith EtOAc (100 mL) and water (100 mL), and filtered through Celite. Thelayers were separated and the aqueous phase was neutralized (pH=7) withsaturated Na₂CO₃ solution. The resulting aqueous phase was extractedwith EtOAc (100 mL) and the mixture was filtered through Celite. Thephases were separated and the aqueous phase was again extracted andfiltered. The combined organic layers were washed with brine (250 mL),dried (MgSO₄), and concentrated to give a brown solid. The crude residuewas purified by trituration in hot toluene to furnish 2.22 g (4.95 mmol,49%) of a tan solid as 1: ¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J=5.8 Hz,1H), 8.07 (br d, J=4.7 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.44 (app dd,J=8.8, 20.6 Hz, 4H), 7.05 (m, 3H), 6.78 (dd, J=2.2, 8.5 Hz, 1H), 3.51(s, 3H), 3.00 (d, J=5.2 Hz, 3H); mp 251-254° C. dec.; LCMS m/z 452.2(MH⁺), t_(R)=2.17 min.

Examples 121-384

The compounds shown in the following Table 3 (Examples 121-384) wereprepared from following the procedure described for Example 120a.

TABLE 3 Example Structure Name MH+ 121

4-[(2-{[4-chloro-3-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.1122

N-methyl-4-[(1-methyl-2-{[4- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 442 123

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl- carboxamide 452.0 124

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 408.1 125

(4-{2-[(4-iodophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 500.1 126

N-methyl(4-{1-methyl-2-[(4- methylphenyl)amino] benzimidazol-5-yloxy}(2-pyridyl))carboxamide 388.2 127

N-methyl(4-{1-methyl-2-[(4- phenoxyphenyl)amino] benzimidazol-5-yloxy}(2-pyridyl))-carboxamide 466.2 128

N-methyl[4-(1-methyl-2-{[4- (trifluoromethoxy)phenyl]amino}benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 458.2 129

(4-{2-[(4-butylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 430.2 130

(4-{2-[(4-bromo-3-fluoro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 470.1 131

N-methyl(4-{1-methyl-2-[(4- nitrophenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))- carboxamide 419.2 132

N-methyl[4-(1-methyl-2-{[4- (methylethyl)phenyl]amino}benzimidazol-5-yloxy)(2- pyridyl)]-carboxamide 416.3 133

(4-{2-[(3,4-dichlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 442.1 134

(4-{2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 466.1 135

(4-{2-[(3,4-dimethylphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 402.2 136

(4-{2-[(3-chloro-4-fluoro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 426.1 137

methyl 4-({1-methyl-5-[2-(N- methylcarbamoyl)(4-pyridyl-oxy)]benzimidazol-2-yl}amino)- benzoate 432.2 138

(4-{2-[(4-bromo-3-chloro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 486.0 139

(4-{2-[(3-bromophenyl)amino]- 1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl- carboxamide 452.1 140

(4-{2-[(4-acetylphenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 416.2 141

[4-(2-{[4-(tert-butyl)phenyl]- amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methyl- carboxamide 430.2 142

(4-{2-[(4-methoxyphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 404.2 143

(4-{2-[(4-cyclohexylphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 456.2 144

(4-{2-[(3,4-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 410.2 145

(4-{2-[(4-methoxy-2-methyl- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 418.2 146

(4-{2-[(3-chlorophenyl)amino]- 1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl- carboxamide 408.1 147

(4-{2-[(3-fluorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 392.2 148

4-({1-methyl-5-[2-(N-methyl- carbamoyl)(4-pyridyloxy)]-benzimidazol-2-yl}amino)- benzoic acid 418.2 149

N-methyl{4-[1-methyl-2- (phenylcarbonylamino)- benzimidazol-5-yloxy](2-pyridyl)}carboxamide 402.2 150

[4-(2-{[2-chloro-5-(trifluoro- methyl)phenyl]amino}-1-methylbenzimidazol-5-yloxy)(2- pyridyl)]-N-methylcarboxamide 476.1 151

(4-{2-[(2,5-dimethoxyphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 434.2 152

(4-{2-[(2,4-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 410.2 153

(4-{2-[(3,5-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 410.2 154

(4-{2-[(4-ethylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 402.2 155

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 408.1 156

(4-{2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 466.1 157

(4-{2-[(2-methoxy-4-nitro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 448.4 158

N-methyl[4-(1-methyl-2-{[2-(tri- fluoromethyl)phenyl]amino}benz-imidazol-5-yloxy)(2-pyridyl)]- carboxamide 441.4 159

(4-{2-[(3-methoxyphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 403.4 160

(4-{2-[(2-ethylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 401.4 161

(4-{2-[(2,5-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 409.3 162

(4-{2-[(2,6-dichlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 442.3 163

(4-{2-[(4-ethylphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 388.2 164

N-methyl(4-{1-methyl-2-[(2- methylthiophenyl)amino]-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 420.1 165

N-methyl(4-{1-methyl-2-[(4- methylthiophenyl)amino]-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 420.1 166

N-methyl[4-(1-methyl-2-{[2- (trifluoromethoxy)phenyl]-amino}benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 458.1 167

[4-(2-{[2-fluoro-5-(trifluoro- methyl)phenyl]amino}-1-methylbenzimidazol-5-yloxy)(2- pyridyl)]-N-methylcarboxamide 460.1 168

(4-{2-[(4-cyanophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methyl- carboxamide 399.1 169

N-methyl[4-(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 442.1 170

N-methyl[4-(1-methyl-2-{[2- (methylethyl)phenyl]amino}-benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 416.2 171

(4-{2-[(5-chloro-2,4-dimethoxy- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 468.2 172

N-methyl(4-{1-methyl-2-[(2- phenylphenyl)amino]benz-imidazol-5-yloxy}(2-pyridyl))- carboxamide 450.2 173

(4-{2-[(3-ethylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 402.2 174

(4-{2-[(2-fluorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 392.1 175

(4-{2-[(4-bromophenyl)amino]- 1-ethylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 466.1 176

(4-{2-[(4-aminophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 389.2 177 (synthesis as in Ex 1)

N-methyl[4-(1-methyl-2-{[4- (methylamino)phenyl]amino}-benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 403.2 178 (synthesis as inEx 1)

[4-(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-benzimidazol-5-yloxy)(2- pyridyl)]-N-methylcarboxamide 417.2 179

N-methyl-4-[(1-methyl-2-{[5- methyl-2-(methyloxy)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 418.5 180

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 434.5 181

4-({2-[(2,6-difluorophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 410.4 182

4-[(2-{[3,5-bis(trifluoromethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 510.4 183

N-methyl-4-[(1-methyl-2-{[4- (methyloxy)-1,1′-biphenyl-3-yl]-amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 480.5 184

4-({2-[(2,4-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 185

4-({2-[(2-chloro-5-nitrophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 453.9 186

N-methyl-4-[(1-methyl-2-{[4- (methyloxy)-2-nitrophenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 449.4 187

4-[(2-{[4-chloro-2-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.9188

4-({2-[(3-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 189

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 392.4 190

4-({2-[(2,3-dimethylphenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 402.5 191

4-[(2-{[5-chloro-2-(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 438.9 192

N-methyl-4-[(1-methyl-2-{[4- (1,3-oxazol-5-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 441.5 193

4-[(2-{[2-(ethyloxy)phenyl]- amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 418.5 194

4-({2-[(2-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 453.3 195

4-{[2-(cyclohexylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 380.5 196

N-methyl-4-({1-methyl-2-[(3- nitrophenyl)amino]-1H-benz-imidazol-5-yl}oxy)pyridine-2- carboxamide 419.4 197

4-({2-[(3-cyanophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 399.4 198

N-methyl-4-[(1-methyl-2-{[4- (1H-pyrazol-1-yl)phenyl]-amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 440.5 199

4-({2-[(2-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 408.9 200

4-{[2-(cyclopropylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 338.4 201

4-[(2-{[4-(ethyloxy)phenyl]- amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 418.5 202

N-methyl-4-{[1-methyl-2-({3- [(phenylmethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl] oxy}-pyridine-2-carboxamide 480.5 203

4-{[2-(2,3-dihydro-1H-inden-5- ylamino)-1-methyl-1H-benz-imidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 414.5 204

4-({2-[(2-ethyl-6-methylphenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 416.5 205

N-methyl-4-{[1-methyl-2-({4- [(4-nitrophenyl)oxy]phenyl}-amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 511.5 206

4-({2-[(cyclohexylmethyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 394.5 207

4-[(2-{[4-bromo-3-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 521.3208

4-{[2-({4-[(Z)-amino(imino)- methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 416.5209

4-({2-[(1-acetyl-2,3-dihydro-1H- indol-6-yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 457.5 210

4-[(2-{[4-fluoro-3-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 460.4211

4-{[2-(cycloheptylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 394.5 212

4-({2-[(3-acetylphenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 416.5 213

4-{[2-(bicyclo[2.2.1]hept-2- ylamino)-1-methyl-1H-benz-imidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 392.5 214

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)-5-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 472.4215

4-[(2-{[4-(1-hydroxyethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-methylpyridine-2-carboxamide 418.5 216

N-methyl-4-({1-methyl-2-[(2- pyrrolidin-1-ylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 395.5 217

N-methyl-4-({1-methyl-2-[(3- morpholin-4-ylpropyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 425.5 218

N-methyl-4-[(1-methyl-2-{[3-(2- oxopyrrolidin-1-yl)propyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 423.5 219

N-methyl-4-[(1-methyl-2-{[2-(1- methylpyrrolidin-2-yl)ethyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 409.5 220

N-methyl-4-({1-methyl-2-[(2- morpholin-4-ylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 411.5 221

4-[(2-{[2,4-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 434.5 222

1,1-dimethylethyl 3-{[1-methyl- 5-({2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-1H-benz- imidazol-2-yl]amino}benzoate 474.5 223

3-{[1-methyl-5-({2-[(methyl- amino)carbonyl]pyridin-4-yl}-oxy)-1H-benzimidazol-2-yl]- amino}benzoic acid 418.4 224

4-({2-[(3,5-dimethylisoxazol-4- yl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 393.4 225

N-methyl-4-({1-methyl-2-[(5- methyl-3-phenylisoxazol-4-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 455.5 226

N-methyl-4-[(1-methyl-2-{[2-(1- methyl-1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 469.6 227

4-({2-[(4-chloro-1H-indazol-3- yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 448.9 228

N-methyl-4-{[1-methyl-2-({[4- (methyloxy)phenyl]methyl}amino)-1H-benzimidazol-5-yl] oxy}-pyridine-2-carboxamide 418.5 229

4-({2-[(2,3-difluorophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 410.4 230

N-methyl-4-({1-methyl-2-[(2- morpholin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 459.5 231

4-({2-[(3-iodophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 500.3 232

N-methyl-4-[(1-methyl-2- {[3,4,5-tris(methyloxy)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 464.5 233

N-methyl-4-({1-methyl-2- [(thien-2-ylmethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 394.5 234

N-methyl-4-({1-methyl-2-[(3- thien-2-yl-1H-pyrazol-5-yl)-amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 446.5 235

4-{[2-(1,3-benzodioxol-5-yl- amino)-1-methyl-1H-benz-imidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 418.4 236

4-({2-[(2-iodophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 500.3 237

4-({2-[(2,6-diethylphenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 430.5 238

4-[(2-{[3-(1-hydroxyethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 418.5 239

4-[(2-{[4-(1H-imidazol-1-yl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 440.5 240

N-methyl-4-[(1-methyl-2-{[2- (phenyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 466.5 241

4-[(2-{[3,4-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 434.5 242

N-methyl-4-[(1-methyl-2-{[2- morpholin-4-yl-5-(trifluoro-methyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine- 2-carboxamide527.5 243

N-methyl-4-({1-methyl-2- [(tricyclo[3.3.1.1~3,7~]dec-1-ylmethyl)amino]-1H- benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 446.6244

4-({2-[1,1′-bi(cyclohexyl)-2- ylamino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 462.6 245

4-{[2-({[(1S,5S)-6,6-dimethyl- bicyclo[3.1.1]hept-2-yl]methyl}-amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 434.6 246

N-methyl-4-{[1-methyl-2- (tricyclo[3.3.1.1~3,7~]dec-1-ylamino)-1H-benzimidazol-5- yl]oxy}pyridine-2-carboxamide 432.5 247

N-methyl-4-({1-methyl-2-[(3- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 388.4 248

4-[(2-{[5-fluoro-2-(1H-imidazol- 1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 458.5 249

N-methyl-4-({1-methyl-2-[(5- phenyl-1H-pyrazol-3-yl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 440.5 250

4-{[2-({4-[(4-ethylpiperazin-1- yl)methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 500.6251

4-({2-[(1,3-dioxo-2,3-dihydro- 1H-isoindol-5-yl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 443.4252

N-methyl-4-({1-methyl-2-[(3- oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 429.4 253

4-({2-[(4-bromophenyl)- (methyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 254

N-methyl-4-{[1-methyl-2- (naphthalen-2-ylamino)-1H-benzimidazol-5-yl]oxy}pyridine- 2-carboxamide 424.5 255

ethyl 1-methyl-5-({2-[(methyl- amino)carbonyl]pyridin-4-yl}-oxy)-1H-benzimidazol-2-yl- carbamate 370.4 256

4-[(2-{[3-(1H-imidazol-1-yl)- propyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 406.5 257

N-methyl-4-({1-methyl-2-[(2- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 388.4 258

4-({2-[(2,6-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 259

4-{[2-({2-[(difluoromethyl)- oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 440.4 260

4-[(2-{[2-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 430.5 261

N-methyl-4-({1-methyl-2- [methyl(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 402.5 262

N-methyl-4-[(1-methyl-2-{[3- (methylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 420.5 263

4-{[2-({4-cyano-2-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 483.4264

N-methyl-4-({1-methyl-2-[(4- {1-[(phenylmethyl)amino]-ethyl}phenyl)amino]-1H- benzimidazol-5-yl}oxy)pyridine- 2-carboxamide507.6 265

4-{[2-(1H-indol-5-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 413.5 266

N-methyl-4-{[1-methyl-2- (phenylamino)-1H-benzimidazol-5-yl]oxy}pyridine- 2-carboxamide 374.4 267

N-methyl-4-[(1-methyl-2-{[2- (phenylcarbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 478.5 268

4-{[2-({4-bromo-2-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 537.3269

4-({2-[(2,4-dibromo-6-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 550.2 270

4-{[2-(1,3-dihydro-2 h-isoindol- 2-yl)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 400.5 271

4-{[2-(isoquinolin-1-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 425.5 272

N-methyl-4-[(1-methyl-2-{[2- (1H-pyrazol-1-yl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 440.5 273

4-{[2-(1H-indol-6-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 413.5 274

methyl 4-{[1-methyl-5-({2- [(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2- yl]amino}-3-[(trifluoromethyl)-oxy]benzoate 516.4 275

4-({2-[(2-cyanophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 399.4 276

N-methyl-4-[(1-methyl-2-{[2- (phenylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 482.6 277

4-[(2-{[2-[(4-chlorophenyl)oxy]- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 569.0 278

N-methyl-4-[(1-methyl-2-{[2- [(4-methylphenyl)oxy]-5-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 548.5 279

4-({2-[(4-chlorophenyl)amino]- 1,7-dimethyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 422.9 280

4-[(2-{[3-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 430.5 281

4-({2-[(3-cyclohexylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 456.6 282

4-({2-[(2,5-dichlorophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 443.3 283

N-methyl-4-[(1-methyl-2-{[2- [2-(methyloxy)phenyl]oxy}-5-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 564.5 284

4-[(2-{[2-[(4-cyanophenyl)oxy]- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 559.5 285

4-({2-[(2,5-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 286

4-({2-[(5-fluoro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 406.4 287

4-({2-[(2-aminophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 389.4 288

4-({2-[(2-cyano-5-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 413.5 289

N-methyl-4-[(1-methyl-2-{[(4- methylphenyl)methyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 402.5 290

4-({2-[(4-bromo-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 291

4-({2-[(5-bromo-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 292

N-methyl-4-({1-methyl-2-[(4- methyl-1,1′-biphenyl-3-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 464.5 293

4-({2-[(5-chloro-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 294

4-[(2-{[5-cyclohexyl-2-(methyl- oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 486.6 295

4-({2-[(4-bromo-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 471.3 296

4-({2-[(2-amino-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 403.5 297

N-methyl-4-{[1-methyl-2- (5,6,7,8-tetrahydronaphthalen-1-ylamino)-1H-benzimidazol-5- yl]oxy}pyridine-2-carboxamide 428.5 298

N-methyl-4-[(1-methyl-2-{[4- (methylsulfonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 452.5 299

N-methyl-4-{[1-methyl-2-({3- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 474.5 300

N-methyl-4-{[1-methyl-2-({4- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 474.5 301

4-{[2-(1,1′-biphenyl-3-ylamino)- 1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2- carboxamide 450.5 302

4-({2-[(2-chloro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 303

4-[(2-{[2-bromo-4-(1-methyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 495.4 304

4-({2-[(3-ethynylphenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 398.4 305

4-{[2-(isoquinolin-7-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 425.5 306

N-methyl-4-[(1-methyl-2-{[3-(1- methylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 416.5 307

4-({2-[(3-bromo-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 308

N-methyl-4-({1-methyl-2- [(phenylsulfonyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 438.5 309

4-{[2-(9H-fluoren-1-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 462.5 310

4-{[2-(9H-fluoren-2-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 462.5 311

4-({2-[(2,2-difluoro-1,3- benzodioxol-5-yl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 454.4312

N-methyl-4-{[1-methyl-2-({3- [(trifluoromethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 458.4 313

N-methyl-4-({1-methyl-2-[(1- methylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 340.4 314

N-methyl-4-({1-methyl-2-[(2- phenylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 402.5 315

4-({2-[(3-cycloheptylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 470.6 316

N-methyl-4-[(1-methyl-2- {[(phenylmethyl)sulfonyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 452.5 317

4-{[2-(2,3-dihydro-1H-indol-6- ylamino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 415.5 318

N-methyl-4-[(1-methyl-2-{[1-(3- pyridin-4-ylpropanoyl)-2,3-dihydro-1H-indol-6-yl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 548.6 319

4-({2-[(3-chloro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 320

4-{[2-(cyclopentylamino)-1- methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2- carboxamide 366.4 321 (synthesis as in Ex 1)

4-[(2-{[4-(diethylamino)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 445.5 322

N-methyl-4-[(1-methyl-2-{[2-(4- methylphenyl)ethyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 416.5 323

4-[(2-{[4-bromo-2-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 521.3324

4-({2-[(4-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 325

4-[(2-{[3-(diethylamino)- propyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 411.5 326

4-({2-[(4-bromo-2-chloro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 487.8 327

4-({2-[(3,5-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 328

4-({2-[(cyclopropylmethyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 352.4 329

4-{[2-(2,3-dihydro-1,4- benzodioxin-6-ylamino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 432.4330

N-methyl-4-[(1-methyl-2-{[4- (phenyloxy)pyridin-3-yl]-amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 467.5 331

N-methyl-4-({1-methyl-2-[(4- pyridin-2-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 451.5 332

4-({2-[(2-chloro-4-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 333

4-({2-[(4-fluoro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 406.4 334

N-methyl-4-({1-methyl-2- [(2,4,5-trimethylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 416.5 335

4-[(2-{[2-chloro-4-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.9336

4-({2-[(5-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 337

4-({2-[(4-chloro-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 338

N-methyl-4-[(1-methyl-2-{[3-(1- methylpropyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 430.5 339

4-({2-[(4-fluoro-3-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 406.4 340

4-({2-[(4-chloro-3-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 341

4-{[2-({3-bromo-4-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 537.3342

4-{[2-({3-chloro-4-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 492.9343

N-methyl-4-({1-methyl-2-[(4- pyridin-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 451.5 344

4-[(2-{[3-chloro-4-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.9345

4-({2-[(4-chloro-3-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 346

4-({2-[(2-bromo-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 347

N-methyl-4-({1-methyl-2- [(2,3,5-trifluorophenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 428.4 348

4-({2-[(2,4-dibromophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 532.2 349

4-({2-[(2-chloro-5-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 350

4-{[2-({3-chloro-4-[(trifluoro- methyl)thio]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 508.9351

4-({2-[(3-chloro-1H-indol-6- yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 447.9 352

4-[(2-{[3,5-bis(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 486.6 353

4-[(2-{[5-(1,1-dimethylethyl)-2- (methyloxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 460.5354

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)-5-(1-methyl-1-phenylethyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 522.6 355

4-[(2-{[4-chloro-2,5-bis(methyl- oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 468.9 356

4-{[2-({4-fluoro-2-[(1-methyl- ethyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 450.5357

N-methyl-4-{[1-methyl-2-({3- [(1-methylethyl)oxy]phenyl}-amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 432.5 358(synthesis as in Ex 769)

4-({2-[(3-furan-3-ylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 440.5 359

4-[(2-{[4-chloro-5-methyl-2- (methyloxy)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 452.9360

N-methyl-4-[(1-methyl-2-{[2- methyl-5-(1-methylethyl)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 430.5 361

4-[(2-{[2,5-bis(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 486.6 362

4-{[2-({5-chloro-2-[(difluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 474.9363

N-methyl-4-{[1-methyl-2-({4- [(phenylmethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl] oxy}-pyridine-2-carboxamide 480.5 364

4-({2-[(2-{[cyclohexyl(methyl)- amino]methyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 499.6365

N-methyl-4-({1-methyl-2-[(6- pyrrolidin-1-ylpyridin-3-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 444.5 366

4-[(2-{[6-(dimethylamino)- pyridin-3-yl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 418.4 367

N-methyl-4-({1-methyl-2-[(1- methylpiperidin-4-yl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 395.4 368

N-methyl-4-({1-methyl-2-[(4- methylcyclohexyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 394.4 369

4-({2-[(cycloheptylmethyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 408.5 370

N-methyl-4-({1-methyl-2- [(3,3,5-trimethylcyclohexyl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 422.5 371

N-methyl-4-({1-methyl-2-[(2- methylcyclohexyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 394.4

Example 372 Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide

The compound4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamidewas synthesized as follows:

Step 1. Synthesis of tert-butyl 4-chloropyridine-2-carboxylate

4-chloropyridine-2-carbonyl chloride (1 eq) was suspended in anhydroustetrahydrofuran. Then 2 equivalents of a solution of 1 M potassiumtert-butoxide was added dropwise to the reaction slowly as the reactionwas stirring under nitrogen. After 3-4 hours or when the reaction wasdetermined to be complete by HPLC, the reaction was evaporated underreduced pressure and diluted with ethyl acetate. The organic layer waswashed with water followed by brine and dried over anhydrous sodiumsulfate. The organic extracts were evaporated under reduced pressure toyield the tert-butyl ester as a yellow oil. MS: MH+=214.0

Step 2. Synthesis of tert-butyl4-(4-amino-3-nitrophenoxy)pyridine-2-carboxylate

Solid anhydrous white powdered KHMDS (2 eq) was suspended in a solutionof dimethylformamide. Red crystalline 4-amino-3-nitrophenol (1 eq) wascharged to the rapidly stirring solution under an inert atmosphere andthe heterogeneous solution was allowed to stir for 2 hours. Then adimethylformamide solution of tert-butyl 4-chloropyridine-2-carboxylate(1 eq) was added dropwise. Anhydrous powdered potassium carbonate (1.2eq) was charged to the reaction as an acid scavenger. The purple coloredviscous mixture was heated to 80° C. for 12-15 hours until when it wasdetermined to be complete by HPLC. The reaction was evaporated underreduced pressure and diluted with excess ethyl acetate and water. Anextraction of the aqueous layer was made with ethyl acetate. The organiclayers were combined and washed 4 times with water followed by brine.The organic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude material was purified by flash silicagel chromatography using an eluent of 1:1 mixture of hexanes to ethylacetate to give the desired product. MS: MH+=332.

Step 3. Synthesis of tert-butyl4-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]pyridine-2-carboxylate

Trifluoroacetic anhydride (1 eq) was slowly added dropwise to a solutionof the above amine in anhydrous methylene chloride under nitrogen. After10-15 minutes or until the reaction was complete as determined by HPLC,the reaction was quenched with excess saturated aqueous sodiumbicarbonate. The product was extracted with methylene chloride from theaqueous layer and washed with water and brine. The extracts were driedover anhydrous sodium sulfate and evaporated under reduced pressure toafford the title product as a yellow solid. MS: MH⁺=428.

Step 4. Synthesis of tert-butyl4-[3-nitro-4-(2,2,2-trifluoro-N-methylacetylamino)phenoxy]pyridine-2-carboxylate

A solution of tert-butyl4-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]pyridine-2-carboxylate(1 eq) and sodium carbonate (4 eq) in dimethylformamide was stirred at20° C. under nitrogen for thirty minutes before 2 equivalents ofiodomethane (2 eq) was charged slowly dropwise to the reaction. After2-3 hours or until it was determined to be complete by HPLC, thereaction was evaporated under reduced pressure. The crude mixture wasdiluted with ethyl acetate and washed with water. The organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure to afford the title product as an orange solid. MS: MH⁺=442.

Step 5. Synthesis of tert-butyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylate

A solution of tert-butyl4-[3-nitro-4-(2,2,2-trifluoro-N-methylacetylamino)phenoxy]pyridine-2-carboxylatein ethanol was stirred at room temperature. 1N sodium hydroxide wasslowly dropped into the reaction until the conversion was complete byHPLC. The reaction was evaporated under reduced conditions and thenextracted with ethyl acetate and washed with a saturated aqueoussolution of ammonium chloride followed by water and brine. The organicextracts were dried over anhydrous sodium sulfate and evaporated underreduced pressure to afford the product as an orange solid. MS: MH⁺=346

Step 6. Synthesis of tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate

A solution of tert-butyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylate (1 eq) and 10%palladium on carbon (0.1 eq) in methanol was stirred at room temperatureand flushed with nitrogen. Hydrogen was flushed through the reaction for1-2 hours or until the reaction was determined to be complete by HPLC.Nitrogen was flushed through the reaction for 15 minutes before thereaction was filtered through a celite pad. The celite pad was washedwith excess methanol followed by concentration under reduced pressure toafford the product as a light yellow solid. MS: MH⁺=316.

Step 7. Synthesis of tert-butyl4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-2-carboxylate

A solution of the diamine from step 6 (1 eq) and 4-bromophenylisothiocyanate (1 eq) in anhydrous tetrahydrofuran under nitrogen wasstirred at 20° C. for 2-3 hours or when determined to be complete byHPLC. The solution was treated with 3 equivalents of1-ethyl-(3-dimethylaminopropyl)carbodiimide HCl. The stirred solutionwas heated to 50° C. under nitrogen for 2-3 hrs or until the reaction isdetermined to be complete by HPLC. The reaction was evaporated underreduced pressure and then diluted with ethyl acetate and water. Theaqueous layer was back extracted with ethyl acetate. The combinedorganic layers were washed with water and brine. The organic layer wasdried over anhydrous sodium sulfate and later evaporated under reducedpressure. The crude material was purified by reverse high-pressureliquid chromatography to afford the product as a brown powder afterlyophlization. MS: MH⁺=495.

Step 8. Synthesis of4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-2-carboxylicacid

A solution of the product of step 7 in trifluoroacetic acid was treatedwith two drops of water at room temperature for 3-4 hours or until thereaction was determined to be complete by HPLC. The reaction wasevaporated under reduced pressure to afford the product as a red-orangeoil in quantitative yield. MS: MH⁺=439.

Step 9. Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide

A solution of above (1 eq) in anhydrous tetrahydrofuran (0.5 ml) wastreated with O-benzotriazol-1-yl N,N,N′,N′-tetramethyl uroniumhexafluorophosphate (2 eq), excess diisopropylethyl amine, and ethylamine (1 eq). The reaction was left stirring under nitrogen for 12-15hours. The reaction was evaporated under reduced pressure and dilutedwith ethyl acetate. The ethyl acetate layer was washed once with waterand then evaporated under reduced pressure. The crude material waspurified by reverse high-pressure liquid chromatography and recovered asTFA salt after lyophilization. MS: MH⁺=466.

Examples 373-447

The compounds shown in the following Table 4 (Examples 373-447) wereprepared from following the procedure described for Example 372.

TABLE 4 Example Structure Name MH+ 373

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(2-hydroxyethyl) pyridine-2-carboxamide 482 374

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}-oxy)-N,N-dimethylpyridine- 2-carboxamide 466 375

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(2,2,2- trifluoroethyl)-pyridine-2- carboxamide 521 376

N-(4-bromophenyl)-1-methyl-5- {[2-(pyrrolidin-1-ylcarbonyl)-pyridin-4-yl]oxy}-1H- benzimidazol-2-amine 492 377

ethyl (3R)-3-(methyloxy)-4-[({4- [(2-{[4-(trifluoromethyl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridin-2-yl}carbonyl)-amino]piperidine-1-carboxylate 599 378

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)- ethyl]pyridine-2-carboxamide 509 379

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(tetrahydrofuran-2- yl-methyl)pyridine-2- carboxamide 522 380

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(2-morpholin-4- ylethyl)-pyridine-2-carboxamide 551 381

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(piperidin-4- ylmethyl)-pyridine-2- carboxamide 535 382

5-({2-[(3-aminopyrrolidin-1-yl)- carbonyl]pyridin-4-yl}oxy)-N-(4-bromophenyl)-1-methyl-1H- benzimidazol-2-amine 507 383

4-({2-[(4-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}-oxy)-N-[1-(diphenyl- methyl)-azetidin-3-yl]pyridine- 2-carboxamide659 384

N-((3S)pyrrolidin-3-yl)(4-{2-[(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 507.0 385

N-(2-aminoethyl)(4-{2-[(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 481.0 386

N-((3R)pyrrolidin-3-yl)(4-{2- [(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2- pyridyl))carboxamide 507.0 387

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2- piperidylethyl)-carboxamide 549.1 388

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(oxolan-2- ylmethyl)-carboxamide 522.0 389

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2- pyrrolidinylethyl)-carboxamide 535.1 390

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(1,3- thiazol-2-yl)-carboxamide 521.0 391

3-aminopyrrolidinyl 4-{2-[(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy} (2-pyridyl) ketone 507.0 392

N-[(3R,5R)-5-(methoxymethyl)- pyrrolidin-3-yl](4-{2-[(4-bromo-phenyl)amino]-1-methyl- benzimidazol-5-yloxy}(2- pyridyl))carboxamide551.1 393

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[(1- ethylpyrrolidin-2-yl)methyl] carboxamide 549.2394

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3- piperidyl)carboxamide 521.0 395

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3- imidazolylpropyl)carboxamide 546.4 396

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(2-oxo- pyrrolidinyl)propyl]carboxamide 563.4397

4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-pyridine-2-carboxamide 438.1 398

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N- (methylethyl)-carboxamide 480.3 399

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4- hydroxycyclohexyl)carboxamide 536.4 400

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2- methoxyethyl)carboxamide 496.3 401

N-(2 h-benzo[d]1,3-dioxolen-5- ylmethyl)(4-{2-[(4- bromophenyl)amino]-1-methylbenzimidazol-5- yloxy}(2-pyridyl))carboxamide 572.4 402

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4- pyridylmethyl)carboxamide 529.3 403

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-(4-pyridyl) ethyl)carboxamide 543.4 404

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(4-methyl- piperazinyl)propyl]carboxamide 578.5 405

4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy} (2-pyridyl)4-(2-oxyethyl) piperazinyl ketone 551.4 406

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-imidazol-4- ylethyl)carboxamide 532.4 407

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl] carboxamide 549.1408

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2- oxoazaperhydro-epin-3-yl) carboxamide 549.1 409

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-indol-3- ylethyl)carboxamide 581.4 410

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N- piperidylcarboxamide 521.1 411

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(2-methoxy- phenyl)ethyl]carboxamide 572.1 412

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(3-methoxy- phenyl)ethyl]carboxamide 572.4 413

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(4-methoxy- phenyl)ethyl]carboxamide 572.4 414

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4-methyl- piperazinyl)carboxamide 536.1 415

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-(4-piperidyl) ethyl)carboxamide 549.4 416

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(phenyl- amino)ethyl]carboxamide 557.4 417

N-{2-[(4-{2-[(4-bromophenyl)- amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonyl- amino]-ethyl}acetamide 523.4 418

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(2-oxo- imidazolidinyl)ethyl] carboxamide 550.4 419

methyl 2-[(4-{2-[(4- bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]- acetate 510.3 420

methyl (2S)-2-[(4-{2-[(4-bromo- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carbonylamino]-3- methylbutanoate552.4 421

(2S)-2-[(4-{2-[(4-bromo- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carbonylamino]-3- carbamoylpropanoicacid 553.3 422

methyl 3-[(4-{2-[(4-bromo- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}-2- pyridyl)-carbonylamino] propanoate 524.3 423

N-((2S)-2-aminopropyl)(4-{2- [(4-bromophenyl)amino]-1-methylbenzimidazol-5- yloxy}(2-pyridyl)) carboxamide 495.3 424

N-((2R)-2-aminopropyl)(4-{2- [(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2- pyridyl))carboxamide 495.3 425

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(pyrrolidin-2-yl- methyl)carboxamide 521.4 426

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N- propylcarboxamide 480.3 427

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-6-yloxy}(2-pyridyl))-N- methylcarboxamide 452.1 428

2-[(4-{2-[(4-bromophenyl) amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl) carbonylamino]acetic acid 496.31 429

(2S)-2-[(4-{2-[(4-bromophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carbonyl- amino]-3-methylbutanoic acid 538.1 430

3-[(4-{2-[(4-bromophenyl) amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonyl- amino]propanoic acid 510.1 431

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(1-methyl(4- piperidyl))carboxamide 535.1 432

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3- methoxypropyl)carboxamide 466.1 433

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-imidazolyl- propyl)carboxamide 502.1 434

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-morpholin- 4-yl-ethyl)carboxamide 507.2 435

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-piperidyl- ethyl)carboxamide 505.2 436

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-morpholin- 4-yl-propyl)carboxamide 521.2 437

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(2-oxo- pyrrolidinyl)propyl]carboxamide 519.2 438

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[(1- ethylpyrrolidin-2-yl) methyl]carboxamide 505.2 439

N-((3R)pyrrolidin-3-yl)(4-{2- [(4-chlorophenyl)amino]-1-methylbenzimidazol-5- yloxy}(2-pyridyl))carboxamide 463.2 440

N-{2-[(4-{2-[(4-chlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonyl- amino]ethyl}acetamide 479.2 441

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-imidazol-4-yl- ethyl)carboxamide 488.2 442

(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl] carboxamide 505.2443

N-[(3R,5R)-5-(methoxymethyl)- pyrrolidin-3-yl](4-{2-[(4-chloro-phenyl)amino]-1-methyl- benzimidazol-5-yloxy}(2- pyridyl))carboxamide507.2 444

(2S)-2-[(4-{2-[(4-chlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carbonyl- amino]propanoic acid 466.1 445

N-(2,3-dihydroxypropyl)(4-{2- [(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy} (2-pyridyl))carboxamide 468.1 446

N-((3S)pyrrolidin-3-yl)(4-{2-[(4- chlorophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 463.2 447 (synthesis as inEx 120a)

(4-{2-[(2-methoxyphenyl) amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N- methylcarboxamide 404.1 448 (synthesis as in Ex483)

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[2-(4-methylpiperazin-1-yl)ethyl]-pyridine-2- carboxamide 595.7 448 (synthesis as in Ex 483)

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide 566.7

Example 450 Preparation of(4-Chloro-phenyl)-{5-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-pyridin-4-yloxy]-1-methyl-1H-benzoimidazol-2-yl}-amine)Step 1. Synthesis of 4-(4-Amino-3-nitro-phenoxy)=puridine-2-carbonitrile

Potassium carbonate (9.00 g) was dried in vacuo with heating, cooled toRT under nitrogen. 4-amino-3-nitrophenol (3.355 g),4-chloro-2-cyanopyridine (3.60 g) and DMSAO (30 mL, anhydrous) wereadded. The system was stirred under nitrogen as it was heated to 103°C., and held at this temperature 1 hr. The reaction was then cooled toRT, poured onto ice/H₂O (500 mL) the precipitate was collected, washed(H₂O), dissolved (EtOAc), dried (Na₂SO₄), filtered and stripped to asolid. This was suspended (Et₂O), collected, air-dried 4.1015 g (73.5%)a second crop was collected (0.5467 gm, 10%). M/z=257 (M+1)

Step 2. Synthesis ofN-[4-(2-Cyano-pyridin-4-yloxy)-2-nitro-phenyl]-2,2,2-trifluoro-N-methyl-acetamide

Potassium carbonate (1.6 g) was dried in vacuo with heating, cooled toRT and suspended in dichloromethane (30 mL) with4-(4-amino-3-nitro-phenoxy)=puridine-2-carbonitrile (2.005 gm) undernitrogen. This was cooled to 0° C. and TFAA (2.2 mL) was added, neat.The starting material goes into solution rapidly as addition is made.After 10 min at 0° C., the mixture was diluted with dichloromethane,washed (H₂O, aq NaCl), dried (K₂CO₃), filtered and stripped to a yellowfoam. M/z=353 (M+1) The product was used without purification.

Iodomethane (0.53 mL) was added to a suspension of potassium carbonate(1.858 g) in DMF (30 mL containing compound 2 (˜7.8 mmole) undernitrogen. The suspension stirred at RT overnight, then poured onto H₂O(300 mL), extracted (Et₂O, 3×150 mL), the combined extracts were washed(H₂O, aq. NaCl), dried (potassium carbonate), filtered and stripped toan orange oil (7.4922 g). M/z=367 (M+1)

Step 3. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbonitrile

NaOH (1 mL, 1N aq) was added dropwise to a solution ofN-[4-(2-cyano-pyridin-4-yloxy)-2-nitro-phenyl]-2,2,2-trifluoro-N-methyl-acetamide(440 mg) in ethanol (6 mL) at RT. After 40 min, the mixture was dilutedwith H₂O (20 mL) and cooled to 0° C. Bright orange crystals werecollected, washed (H₂O) and air-dried 311.1 mg (94%). M/z=271 (M+1)

Step 4. Synthesis of4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile

Palladium on carbon (46 mg 10% w/w) was suspended in MeOH (2 mL) undernitrogen. The resulting suspension was added, under nitrogen, to asuspension of 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carbonitrile(311 mg) in MeOH (3 mL) at RT. The atmosphere was exchanged withhydrogen, and the system stirred vigorously under 1 atm hydrogen for 1hr. The atmosphere was then exchanged for nitrogen, the mixture wasfiltered (celite) and the filtrate was used without further purificationin the next reaction. M/z=2421 (M+1).

4-chlorophenylisothiocyanate (200 mg) was added to a solution ofcompound 5 in MeOH (10 mL). The solution was stirred at reflux for 2hrs. Iodomethane (71 microliters) was added, and stirring continued at67° C., overnight. The mixture was then cooled to RT evaporated todryness, and the residue chromatographed (0.5% NH₄OH, 5% MeOH, 94.5%dichloromethane on silica gel) to isolate a compound of Rf=0.29 (325mg). This was crystallized from dichloromethane/ether to give 127 mg.M/z=376 (M+1)

1HNMR (MeOH-d4) 9.40 ppm s(b) (1H) 8.55 ppm d, d H = 5.7, 0.6 Hz (1H)7.62 ppm m (2 h) 7.42 ppm d, d J = 2.5, 0.6 Hz (1H) 7.43 ppm d (1H) 7.37ppm m (2 h) 7.21 ppm d J = 2.0 Hz (1H) 7.15 ppm d, d J = 5.9, 2.5 Hz(1H) 6.97 ppm d, d J = 8.4, 2.2 hz (1H) 3.80 ppm s (3H)

Step 5. Synthesis of(4-Chloro-phenyl)-{5-[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yloxy]-1-methyl-1H-benzoimidazol-2-yl}-amine

H₂SO₄ (454 mg) was added cautiously to a suspension of4-[2-(4-chlorophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile(60.0 mg) in ethylenediamine (0.50 mL). The system was shaken at roomtemperature for 72 hrs, then poured onto ice/NaHCO₃. The solid productwas collected, washed (H₂O) air-dried 59.8 mg. M/z=419 (M+1).

Example 451 Synthesis of(4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamideStep 1. Synthesis of 2-amino-4-methoxyphenol

The mixture containing 4-methoxy-2-nitrophenol in methanol withcatalytic amount of 10% Pd/C was hydrogenated until disappearance ofyellow color to yield 2-amino-4-methoxyphenol. MS: MH+=140.

Step 2. Synthesis of 5-methoxybenzoxazole-2-thiol

The mixture containing 2-amino-4-methoxyphenol (1 eq) and O-ethylxanthicacid, potassium salt (1.1 eq) in pyridine was refluxed for two hours.The resultant mixture was poured in to ice/water containing hydrochloricacid to yield a 5-methoxybenzoxazole-2-thiol as a tan solid. MS: MH+=182

Step 3. Synthesis of 2-chloro-5-methoxybenzoxazole

The mixture containing 5-methoxybenzoxazole-2-thiol was heated inthionyl chloride with a drop of DMF. The resultant mixture wasconcentrated and partitioned between ethyl acetate and water. Theorganic layer was washed with brine and dried and concentrated.Purification on a silica gel column gave 2-chloro-5-methoxybenzoxazoleas a white solid. MS: MH+=184.

Step 4. Synthesis of (4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine

The mixture containing 2-chloro-5-methoxybenzoxazole (1 eq),4-bromoaniline (2 eq) and diisopropylethylamine was refluxed indimethylformamide. The resultant mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried. Purification on silica gel gave(4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine. MS: MH+=318

Step 5. Synthesis of 2-[(4-bromophenyl)amino]benzoxazol-5-ol

The mixture of (4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine andhydrobromic acid (48%) was subjected to the microwave at 150° C. for 6mins to yield 2-[(4-bromophenyl)amino]benzoxazol-5-ol. MS: MH+=305

Step 6. Synthesis of(4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide

The mixture containing 2-[(4-bromophenyl)amino]benzoxazol-5-ol (1 eq),potassium bis(trimethylsilyl)amide (4 eq), was stirred indimethylformamide for 30 min at room temperature. To this mixture wasadded (4-chloro(2-pyridyl)-N-methylcarboxamide (1 eq) and Potassiumcarbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reactionmixture was then concentrated and partitioned between ethyl acetate andwater. The organic layer was separated and washed with brine, dried,filtered and concentrated. Purification on Prep LC yielded the desiredproduct. MS: MH+=439.

The compounds shown in the following Table 5 (Examples 452-481) wereprepared from following the procedure described for Examples 449-451.

TABLE 5 Example Structure Name MH+ 452

N-(2-aminoethyl)-4-({2-[(4-bromo- phenyl)amino]-1,3-benzoxazol-5-yl}oxy)pyridine-2-carboxamide 469.3 453

4-({2-[(4-bromophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2- carboxamide 539.4 454

4-({2-[(4-bromophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3-yl]pyridine-2- carboxamide 495.3 455

4-({2-[(4-bromophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-{(3R,SR)-5-[(methyloxy)methyl]pyrrolidin-3- yl}pyridine-2-carboxamide 539.4 456

4-({2-[(4-chlorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 395.8 457

4-({2-[(3,5-difluorophenyl)amino]- 1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 397.4 458

N-methyl-4-[(2-{[2-(trifluoro- methyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2- carboxamide 429.4 459

4-({2-[(2-fluorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 379.4 460

4-({2-[(2,6-difluorophenyl)amino]- 1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 397.4 461

N-methyl-4-[(2-{[3-(trifluoro- methyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2- carboxamide 429.4 462

4-({2-[(2-chlorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 395.8 463

4-({2-[(2-ethylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 389.4 464

N-methyl-4-[(2-{[4-(1-methyl- ethyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2- carboxamide 403.5 465

4-({2-[(3-chlorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 395.8 466

N-methyl-4-{[2-({4-[(trifluoro- methyl)oxy]phenyl}amino)-1,3-benzoxazol-5-yl]oxy}pyridine-2- carboxamide 445.4 467

N-methyl-4-[(2-{[2-(1-methyl- ethyl)phenyl]amino}-1,3-ben-zoxazol-5-yl)oxy]pyridine-2- carboxamide 403.5 468

4-({2-[(3,4-dichlorophenyl)amino]- 1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 430.3 469

4-({2-[(4-ethylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 389.4 470

4-[(2-{[4-(1-methylethyl)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2- carboxamide 458.5 471

4-({2-[(2,5- dimethylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 389.4 472

4-({2-[(4-bromophenyl)(methyl)- amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 454.3 473

N-methyl-4-{[2-(phenylamino)-1,3- benzoxazol-5-yl]oxy}pyridine-2-carboxamide 361.4 474

4-[(2-{[4-(dimethylamino)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 404.4 475

4-[(2-{[4-(4-ethylpiperazin-1-yl)- phenyl]amino}-1,3-benzoxazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 473.5 476

4-({2-[(4-butylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 417.5 477

N-methyl-4-[(2-{[4-(phenyloxy)- phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2-carboxamide 453.5 478

4-[(2-{[4-(1-methylethyl)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-(2-morpholin-4-ylethyl)pyridine- 2-carboxamide 502.6 479

N-[1-(1-methylethyl)azetidin-3-yl]- 4-[(2-{[4-(1-methylethyl)phenyl]-amino}-1,3-benzoxazol-5-yl)oxy]- pyridine-2-carboxamide 486.6 480

4-({2-[(4-bromo-3-fluorophenyl)- amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 458.3 481

4-[(2-{[4-(1-methylethyl)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-[2-(2-oxoimidazolidin-1-yl)- ethyl]pyridine-2-carboxamide 501.6

Example 482 Synthesis of [4-(2-{[4-(dimethylamino)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamideStep 1. Synthesis of4-(2-{[4-(dimethylamino)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridinr-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-(dimethylamino)benzeneisothiocyanate (1 eq)and stir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. The mixture was then concentrated and toit was added tetrahydrofuran and1-ethyl-(3-dimethylaminopropyl)carbodimidehydrochloride (2 eq) and stirat ambient temperature for 16 h.tert-butyl4-(2-{[4-dimethylamino)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatecrashes out of the reaction mixture. To it in methylene chloride wasadded trifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-dimethylamino)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=403.

Step 2. Synthesis of[4-(2-{[4-(dimethylamino)phenylamino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

To4-(2-{[4-(dimethylamino)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[4-(dimethylamino)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=498.

Example 483 Synthesis of [4-(2-{[4-bromo-3-methylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamideStep 1. Synthesis of4-{2-[(4-bromo-3-methylphenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq)and stir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=452

Step 2. Synthesis of[4-(2-{[4-bromo-3-methylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

To4-(2-{[4-bromo-3-methylpheylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[4bromo-3-methylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=549.

Example 484 Synthesis of[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamideStep 1. Synthesis of4-{2-[(2-fluoro-5-(trifluoromethyl)phenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) and stir atambient temperature for 16 h. Formation of the corresponding thioureawas followed by LC/MS. To it was then added iodomethane (1 eq) andheated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[2-fluoro-5-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=446.

Step 2. Synthesis of[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

To4-(2-{[2-fluoro-5-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)-(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=542.

Example 485 Synthesis of[4-(2-{[4-bromo-3-fluorophenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamideStep 1. Synthesis of4-{2-[(4-bromo-3-fluorophenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-bromo-3-fluorobenzeneisothiocyanate (1 eq)and stir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-bromo-3-fluorophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-bromo-3-fluorophenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=456.

Step 2. Synthesis of[4-(2-{[4-bromo-3-fluorophenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

To4-(2-{[4-bromo-3-fluorophenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[4-bromo-3-fluorophenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide.MS: MH⁺=567.

Example 486 Synthesis of4-{1-methyl-2-[(4-methylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamideStep 1. Synthesis of4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylicacid

To tert-butyl-4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate(1 eq) in methanol was added 4-methylbenzeneisothiocyanate (1 eq) andstir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl-4-{1-methyl-2-[(4-methylphenyl)amino)benzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=374.

Step 2. Synthesis of4-{1-methyl-2-[(4-methylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

To4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded4-{1-methyl-2-[(4-methylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-2(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=470.

Example 487 Synthesis of [4-(2-{[4-ethylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamideStep 1. Synthesis of4-{2-[(4-ethylphenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-ethylbenzeneisothiocyanate (1 eq) and stirat ambient temperature for 16 h. Formation of the corresponding thioureawas followed by LC/MS. To it was then added iodomethane (1 eq) andheated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-ethylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-ethylphenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=388.

Step 2. Synthesis of[4-(2-{[4-ethylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

To4-(2-{[4-ethylphenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[4-ethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=484.

Example 488 Synthesis of[4-(2-{[3-(tert-butyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamideStep 1. Synthesis of4-{2-[(3-(tert-butyl)phenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 3-(tert-butyl)benzeneisothiocyanate (1 eq) andstir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[3-(tert-butyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[3-(tert-butyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=416.

Step 2. Synthesis of[4-(2-{[3-(tert-butyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

To4-(2-{[3-(tert-butyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[3-(tert-butyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide.MS: MH⁺=512.

Example 489 Synthesis of[4-(2-{[4-chloro-3-(trifluoromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamideStep 1. Synthesis of4-{2-[(4-chloro-3-(trifluoromethyl)phenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added4-chloro-3-(trifluoromethyl)benzeneisothiocyanate (1 eq) and stir atambient temperature for 16 h. Formation of the corresponding thioureawas followed by LC/MS. To it was then added iodomethane (1 eq) andheated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-chloro-3-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=462.

Step 2. Synthesis of[4-(2-{[4-chloro-3-(trifluoromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

To4-(2-{[4-chloro-3-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[4-chloro-3-trifluoromethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide.MS: MH⁺=558.

Each of the compounds 490-626 listed below in Table 6, were synthesizedas indicated in the right hand column by the method described in one ofthe Examples 482-489.

TABLE 6 Synthe- Ex- sized as am- in Ex- ple Molecular Structure Name MH+ample: 490

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[(1-ethylpyrrolidin-2-yl)-methyl]pyridine-2-carbox- amide 514.6 482 491

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide 516.6 482 492

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2- carboxamide 543.7 482 493

4-[2-{[4-(c1imethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-1,3-thiazol-2-ylpyridine- 2-carboxamide486.6 482 494

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carbox- amide 514.6 482 495

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide 500.6 482 496

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carbox- amide 511.6 482 497

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide 461.5 482 498

4-{(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-hydroxyethyl)- pyridine-2-carboxamide447.5 482 499

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-piperidin-1-ylethyl)-pyridine-2-carboxamide 514.6 482 500

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(3-piperidin-1-ylpropyl)-pyridine-2-carboxamide 528.7 482 501

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(3-pyrrolidin-1-ylpropyl)-pyridine-2-carboxamide 514.6 482 502

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide 508.6 482 503

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-propylpyridine-2-carbox- amide 445.5 482504

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide 515.6 482 505

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(methyloxy)propyl]-pyridine-2-carboxamide 475.6 482 506

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-ethylpyridine-2-carbox- amide 431.5 482 507

N-[2-(acetylamino)ethyl]-4- [(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 488.6 482 508

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[2-(2-oxoimidazolidin-1-yl)ethyl]pyridine-2-carbox- amide 515.6 482 509

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-{(3R)-pyrrolidin-3-yl]-pyridine-2-carboxamide 472.6 482 510

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2- carboxamide 528.6 482 511

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2- oxopyrrolidin-1- yl)propyl]pyridine-2- carboxamide578.5 483 512

N-[2-(acetylamino)ethyl]-4- ({2-[(4-bromo-3- methylphenyl)amino]-1-methyl-1H-benzimidazol-5- yl}oxy)pyridine-2- carboxamide 538.4 483 513

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2- carboxamide 481.4 483 514

4-({2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl- 1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4- ylethyl)pyridine-2-carbox- amide 566.5 483 515

4-({2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl- 1H-benzimidazol-5-yl}oxy)-N-[2- (methyloxy)ethyl]pyridine- 2-carboxamide 511.4 483 516

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4- methylpiperazin-1- yl)propyl]pyridine-2- carboxamide593.5 483 517

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin- 3-yl]pyridine-2-carbox- amide 522.4 483 518

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]- pyridine-2-carboxamide564.5 483 519

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(1H-imidazol- 1-yl)propyl]pyridine-2- carboxamide 561.5 483520

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-yl- pyridine-2-carboxamide 536.4 483 521

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine- 2-carboxamide 495.4 483 522

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1- ylethyl)pyridine-2-carbox- amide 550.5 483523

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-hydroxyethyl)pyridine-2-carboxamide 490.4 484 524

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol- 5-yl)oxy]-N-[3-(2- oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 571.5 484 525

N-[2-(acetylamino)ethyl]-4- [(2-{[2-fluoro-5- (trifluoromethyl)-phenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 531.5 484 526

N-ethyl-4-[(2-{[2-fluoro-5- (trifluoromethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 474.4 484 527

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-morpholin-4-yl-ethyl)pyridine-2-carbox- amide 559.5 484 528

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[2-(methyloxy) ethyl]-pyridine-2-carboxamide 504.5 484 529

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- [3-(4-methylpiperazin-1- yl)propyl]pyridine-2-carboxamide 586.6 484 530

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl] pyridine-2-carboxamide 557.6 484 531

N-[2-(dimethylamino)- ethyl]-4-[(2-{[2-fluoro-5- (trifluoromethyl)-phenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 517.5 484 532

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2-carbox- amide 554.5 484 533

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}- 1-methyl-1H-benzimidazol-5-yl)oxy]-N- 1,3-thiazol-2-ylpyridine-2- carboxamide 529.5484 534

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2- pyridin-4-ylethyl)-pyridine-2-carboxamide 551.5 484 535

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-propylpyridine-2- carboxamide488.5 484 536

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}- 1-methyl-1H-benzimidazol-5-yl)oxy]-N- (2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide 543.5 484 537

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[(1-ethyl- pyrrolidin-2-yl)methyl] pyridine-2-carboxamide568.5 485 538

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]- pyridine-2-carboxamide568.5 485 539

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2- (methyloxy)ethyl]pyridine- 2-carboxamide 515.4 485 540

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-(2-piperidin-1- ylethyl)pyridine-2- carboxamide 568.5 485 541

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4- ylethyl)pyridine-2- carboxamide 562.4 485 542

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carbox- amide 529.4 485 543

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine- 2-carboxamide 499.4 485 544

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2- carboxamide 485.3 485 545

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin- 3-yl]pyridine-2-carbox- amide 526.4 485 546

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2- oxopyrrolidin-1- yl)propyl]pyridine-2- carboxamide582.4 485 547

N-[(1-ethylpyrrolidin-2- yl)methyl]-4-({1-methyl-2-[(4-methylphenyl)amino]- 1H-benzimidazol-5-yl}- oxy)pyridine-2-carbox-amide 485.6 486 548

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl) pyridine-2-carboxamide 487.6 486 549

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1- yl)propyl]pyridine-2- carboxamide 514.6 486 550

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-ylpyridine-2- carboxamide 457.5 486 551

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[2-(1-methylpyrrolidin-2- yl)ethyl]pyridine-2- carboxamide 485.6 486 552

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1- ylethyl)pyridine-2- carboxamide 471.6 486 553

N-[2-(dimethylamino)- ethyl]-4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2- carboxamide 445.5 486 554

N-[3-(1H-imidazol-1- yl)propyl]-4-({1-methyl-2- [(4-methylphenyl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2- carboxamide 482.6 486 555

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]- pyridine-2-carboxamide 432.5 486 556

N-(2-hydroxyethyl)-4-({1- methyl-2-[(4-methyl- phenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 418.5 486 557

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(2-piperidin-1-ylethyl) pyridine-2-carboxamide 485.6 486 558

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1- yl)propyl]pyridine-2- carboxamide 499.6 486 559

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(3-piperidin-1-ylpropyl) pyridine-2-carboxamide 499.6 486 560

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(3-pyrrolidin-1-ylpropyl) pyridine-2-carboxamide 485.6 486 561

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(2-pyridin-4-yl- ethyl)pyridine-2-carboxamide 479.6 486 562

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(2-piperazin-1-yl- ethyl)pyridine-2-carboxamide 486.6 486 563

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carbox- amide 446.5 486 564

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-propylpyridine-2- carboxamide 416.5 486 565

N-ethyl-4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 402.5 486 566

N-[2-(acetylamino)ethyl]-4- ({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 459.5 486 567

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-yl)ethyl]pyridine-2- carboxamide 486.5 486 568

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3- yl]pyridine-2-carboxamide 443.5 486 569

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-[(1-ethylpyrrolidin-2- yl)methyl]pyridine-2- carboxamide 499.6 487 570

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)- pyridine-2-carboxamide 501.6 487 571

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1- yl)propyl]pyridine-2- carboxamide 528.7 487 572

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-ylpyridine-2- carboxamide 471.6 487 573

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-[2-(1-methylpyrrolidin-2- yl)ethyl]pyridine-2- carboxamide 499.6 487 574

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)- pyridine-2-carboxamide 485.6 487 575

N-[2-(dimethylamino)- ethyl]-4-({2-[(4-ethyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 459.6 487 576

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-[3-(1H-imidazol-1-yl)- propyl]pyridine-2-carbox- amide 496.6 487 577

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]- pyridine-2-carboxamide 446.5 487 578

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2- carboxamide 432.5 487 579

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(2-piperidin-1-ylethyl)- pyridine-2-carboxamide 499.6 487 580

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(3-piperidin-1-ylpropyl)- pyridine-2-carboxamide 513.7 487 581

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(3-pyrrolidin-1-yl- propyl)pyridine-2-carbox- amide 499.6 487 582

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 493.6 487 583

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-(2-piperazin-1-ylethyl)- pyridine-2-carboxamide 500.6 487 584

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-[3-(methyloxy)propyl]- pyridine-2-carboxamide 460.5 487 585

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-propylpyridine-2- carboxamide 430.5 487 586

N-ethyl-4-({2-[(4-ethyl- phenyl)amino]-1-methyl- 1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide 416.5 487 587

N-[2-(acetylamino)ethyl]-4- ({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol- 5-yl}oxy)pyridine-2- carboxamide 473.5 487 588

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidin-1- yl)ethyl]pyridine-2- carboxamide 500.6 487 589

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[(1-ethyl- pyrrolidin-2-yl)methyl]-pyridine-2-carboxamide 527.7 488 590

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-morpholin-4- ylethyl)pyridine-2-carboxamide 529.7 488 591

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[3-(4-methyl- piperazin-1-yl)propyl]pyridine-2-carboxamide 556.7 488 592

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-1,3-thiazol-2-yl-pyridine-2-carboxamide 499.6 488 593

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl]- pyridine-2-carboxamide 527.7 488 594

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carbox- amide 513.7 488 595

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2- carboxamide 524.6 488 596

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1- ethyl-1H-benzimidazol-5-yl)oxy]-N-[2-(methyloxy) ethyl]pyridine-2-carboxamide 474.6 488 597

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-hydroxyethyl)pyridine-2-carboxamide 460.5 488 598

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-piperidin-1-yl-ethyl)pyridine-2-carboxamide 527.7 488 599

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[3-(2-oxo- pyrrolidin-1-yl)propyl]pyridine-2-carboxamide 541.7 488 600

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(3-piperidin-1-yl-propyl)pyridine-2- carboxamide 541.7 488 601

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(3-pyrrolidin-1-ylpropyl)pyridine-2- carboxamide 527.7 488 602

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-pyridin-4- ylethyl)pyridine-2-carboxamide 521.6 488 603

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-piperazin-1-ylethyl)pyridine-2-carbox- amide 528.7 488 604

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide 488.6 488 605

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-propylpyridine-2- carboxamide 458.6488 606

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-ethylpyridine-2- carboxamide 444.5488 607

N-[2-(acetylamino)ethyl]-4- [(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 501.6 488 608

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[2-(2-oxo- imidazolidin-1-yl)ethyl]-pyridine-2-carboxamide 528.6 488 609

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carbox- amide 485.6 489 610

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl] pyridine-2-carboxamide 574.0 489 611

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- [3-(1H-imidazol-1-yl)propyl]pyridine-2-carboxamide 571.0 489 612

4-[(2-{[4-chloro-3- trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- [2-(dimethylamino)ethyl]pyridine-2-carboxamide 534.0 489 613

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- [3-(methyloxy)propyl]- pyridine-2-carboxamide534.9 489 614

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-propylpyridine-2- carboxamide504.9 489 615

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-ethylpyridine-2- carboxamide 490.9489 616

N-[2-(acetylamino)ethyl]-4- [(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1- methyl-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 547.9 489 617

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide 576.0 489 618

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[3-(4-methyl-piperazin-1-yl)propyl] pyridine-2-carboxamide 603.1 489 619

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide 560.0 489 620

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- [2-(methyloxy)ethyl]- pyridine-2-carboxamide520.9 489 621

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (2-piperidin-1-ylethyl)-pyridine-2-carboxamide 574.0 489 622

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (3-piperidin-1-yl- propyl)pyridine-2-carbox-amide 588.0 489 623

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (2-pyridin-4-ylethyl)- pyridine-2-carboxamide568.0 489 624

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (2-piperazin-1-ylethyl)-pyridine-2-carboxamide 575.0 489 625

4-[(2-{[4-chloro-3-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-[(3R)-pyrrolidin-3-yl]-pyridine-2-carboxamide 531.9 489 626

4-[(2-{[4-chloro-3- (trifluoromethyl)phenyl] amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- [3-(2-oxopyrrolidin-1- yl)propyl]pyridine-2-carboxamide 588.0 489

Example 627 Step 1. Synthesis of[4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

A solution of sodium thiocyanate (1 eq) in acetone was added slowly into a solution of 4-(chloromethyl)benzoylchloride (1 eq) in acetone at 0°C. The mixture was then filtered in to a solution of{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) in acetone. Formation of N-acylthiourea was followed by LC/MS. Themixture was concentrated and taken in tetrahydrofuran and to it wasadded 1-ethyl-(3-dimethylaminopropyl)carbodimidehydrochloride (2 eq) andstirred at ambient temperature for 16 h. The mixture was concentratedand partitioned between ethyl acetate and water. The organic layer wasthen dried and concentrated to yield[4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH⁺=449.

Step 2. Synthesis of N-methyl{4-[1-methyl-2-({4-[(4methylpiperazinyl)methyl]phenyl}carbonylamino)benzimidazol-5-yloxy](2-pyridyl)}carboxamide

To a solution of[4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide(1 eq) in tetrahydrofuran was added methylpiperazine (4 eq) and stirredat ambient temperature for 16 h. The reaction mixture was concentratedand purified on preparative chromatography to yield N-methyl{4-[1-methyl-2-({4-[(4-methylpiperazinyl)methyl]phenyl}carbonylamino)benzimidazol-5-yloxy](2-pyridyl)}carboxamide.MS: MH+=512.

Example 628 Step 1. Synthesis ofN-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)methylphenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide

To a solution of{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) in tetrhydrofuran was added 4-(chloromethyl)benzoylchloride (1 eq)and triethylamine (2 eq). N-acylation is completed in 0.5 h. Thereaction mixture was concentrated and partitioned between ethyl acetateand water. The organic layer was concentrated and to the crude productwas added methylpiperazine (4 eq) and tetrahydrofuran and stir for 16 hat ambient temperature. The reaction mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and taken in acetic acid and heated to 60° C. for 3 h.Preparative chromatography yieldedN-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)methylphenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide.MS: MH⁺=470.

Example 629 Step 1. Synthesis of 2-chloro-4-(3-pyridyl)pyrimidine

Nitrogen was bubbled through a solution of 2,4-dichloropyrimidine (1 eq)in tetrahydrofuran and water (3:1) for 0.5 h.Bis(diphenylphosphino)ferrocene Palladium(II)chloride (0.05 eq) followedby pyridine-3-boronic acid (1 eq) and sodium carbonate (3 eq) was addedand the mixture was heated to 60° C. for 16 h under nitrogen. Thereaction mixture was concentrated and partitioned between ethyl acetateand water. The organic layer was washed with brine and dried with sodiumsulfate and concentrated. Purification on silica gel gave2-chloro-4-(3-pyridyl)pyrimidine. MS: MH⁺=190.

Step 2. Synthesis of2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine

A solution of 4-amino-3-nitro-phenol (1 eq) and2-chloro-4-(3-pyridyl)pyrimidine (1 eq) in N,N-dimethylformamide wasmicrowaved at 150° C. for 10 mins. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was concentrated andpurified on silica gel to yield2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine. MS: MH⁺=309.

Step 3. Synthesis of4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine

The mixture containing2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine in methanol withcatalytic amount of 10% Pd/C was hydrogenated until disappearance ofyellow color to yield4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine. MS: MH⁺=279.

Step 3. Synthesis of{4-[(4-methylpiperazinyl)methyl]phenyl}-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide.

A solution of sodium thiocyanate (1 eq) in acetone was added slowly into a solution of 4-(chloromethyl)benzoylchloride (1 eq) in acetone at 0°C. The mixture was then filtered in to a solution of4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine (1 eq) in acetone.Formation of N-acylthiourea was followed by LC/MS. The mixture wasconcentrated and taken in tetrahydrofuran and to it was added1-ethyl-(3-dimethylaminopropyl)carbodimidehydrochloride (2 eq) andstirred at ambient temperature for 16 h. The mixture was concentratedand partitioned between ethyl acetate and water. The organic layer wasthen dried and concentrated to yield[4-(chloromethyl)phenyl]-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide.It was taken in tetrahydrofuran and added methylpiperazine (4 eq) andstirred at ambient temperature for 16 h. The reaction mixture wasconcentrated and purified on preparative chromatography to yield{4-[(4-methylpiperazinyl)methyl]phenyl}-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide.MS: MH⁺=520.

Example 630 Step 1. Synthesis of4-ethyl-1-[(4-nitrophenyl)methylpiperazine

To 4-(chloromethyl)-1-nitrobenzene (1 eq) in tetrahydrofuran was addedEthylpiperazine (3 eq) and stir for 16 h at ambient temperature.Concentrating and passing through a plug of silica gave4-ethyl-1-[(4-nitrophenyl)methylpiperazine. MS: MH⁺=249

Step 2. Synthesis of 4-[(4-ethylpiperazinyl)methyl]phenylamine

The mixture containing 4-ethyl-1-[(nitrophenyl)methylpiperazine inmethanol with catalytic amount of 10% Pd/C was hydrogenated to yield4-[(4-ethylpiperazinyl)methyl]phenylamine. MS: MH⁺=219.

Step 3. Synthesis of 4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate

To 4-[(4-ethylpiperazinyl)methyl]phenylamine in acetone at 0° C. wasadded sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate. MS: MH⁺=261.

Step 4. Synthesis of[4-[(2-{[4-ethylpiperazinyl)methyl]phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

To 4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate (1 eq) inmethanol was added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and heated to 60° C. for 16 h. Preparative chromatography yielded[4-[(2-{[4-ethylpiperazinyl)methyl]phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH⁺=499.

Example 631 Step 1. Synthesis of 4-Ethyl-1-(4-nitrophenyl)piperazine

To 4-fluoro-1-nitrobenzene (1 eq) in N,N-dimethylformamide was addedEthyl piperazine (2 eq) and N,N-diisopropylethyl amine (2 eq) and heatedat 80° C. for 16 h. Concentrated the resultant mixture and partitionedbetween ethyl acetate and water. The organic layer was then washed withbrine and dried with sodium sulfate and concentrated. Passed through aplug of silica to yield 4-Ethyl-1-(4-nitrophenyl)piperazine. MS:MH⁺=235.

Step 2. Synthesis of 4-(4-ethylpiperazinyl)phenylamine

The mixture containing 4-ethyl-1-(4-nitrophenyl)piperazine in methanolwith catalytic amount of 10% Pd/C was hydrogenated to yield4-(4-ethylpiperazinyl)phenylamine. MS: MH⁺=205.

Step 3. Synthesis of 4-(4-ethylpiperazinyl)benzeneisothiocyanate

To 4-(4-ethylpiperazinyl)phenylamine in acetone at 0° C. was addedsodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4-(4-ethylpiperazinyl)benzeneisothiocyanate. MS: MH⁺=247.

Step 3. Synthesis of[4-(2-{[4-ethylpiperazinyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

To 4-(4-ethylpiperazinyl)benzeneisothiocyanate (1 eq) in methanol wasadded{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and heated to 60° C. for 16 h. Preparative purification yielded[4-(2-{[4-ethylpiperazinyl)phenyl]-amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH⁺=485.

Example 632 Step 1. Synthesis of 4-(2-bromoethyl)-1-nitrobenzene

To 4-(2-bromoethyl)-1-nitrobenzene (1 eq) in tetrahydrofuran was addedmorpholine (3 eq) and stir for 16 h at ambient temperature.Concentrating and passing through a plug of silica gave4-[2-(4-nitrophenyl)ethylmorpholine. MS: MH⁺=236.

Step 2. Synthesis of 4-(2-morpholin-4-ylethyl)phenylamine

The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanolwith catalytic amount of 10% Pd/C was hydrogenated to yield4-(2-morpholin-4-ylethyl)phenylamine. MS: MH⁺=206.

Step 3. Synthesis of 4-(2-morpholin-4-ylethyl)benzeneisothiocyanate

To 4-(2-morpholin-4-ylethyl)phenylamine in acetone at 0° C. was addedsodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4(2-morpholin-4-ylethyl)benzeneisothiocyanate. MS: MH⁺=252.

Step 4. Synthesis ofN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]amino}-benzimidazol-5-oxy)(2-pyridyl)]carboxamide

To 4(2-morpholin-4-ylethyl)benzeneisothiocyanate (1 eq) in methanol wasadded{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and stirred at ambient temperature for 16 h. The correspondingthiourea formation was followed by LC/MS. To it was the addediodomethane (1 eq) and heated to 60° C. for 3 h. Concentration followedby preparative chromatography yieldedN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]amino}-benzimidazol-5-oxy)(2-pyridyl)]carboxamide.MS: MH⁺=486.

Example 633 Step 1. Synthesis of [(4-nitrophenyl)ethyl]benzylamine

To a solution of 1-(4-nitrophenyl)ethan-1-one (1 eq) andphenylmethylamine (1 eq) in methanol was added sodiumtriacetoxyborohydride (1.2 eq). The resulting mixture was stirred atambient temperature for 16 h. The mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative purification yielded[(4-nitrophenyl)ethyl]benzylamine. MS: MH⁺=256.

Step 2. Synthesis of [(4-aminophenyl)ethyl]benzylamine

The mixture containing [(4-nitrophenyl)ethyl]benzylamine in methanolwith catalytic amount of 10% Pd/C was hydrogenated until disappearanceof yellow color to yield [(4-aminophenyl)ethyl]benzylamine. MS: MH⁺=226.

Step 3. Synthesis of 4-{[benzylamino]ethyl}benzeneisothiocyanate

To [(4-nitrophenyl)ethyl]benzylamine in acetone at 0° C. was addedsodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4-{[benzylamino]ethyl}benzeneisothiocyanate. MS: MH⁺=268.

Step 4. Synthesis ofN-methyl(4-{1-methyl-2-2[(4-{[benzylamino]ethyl}-phenyl)amino)benzimidazol-5-yloxy)-(2-pyridyl))carboxamide

To a solution of[4-(3,4-diaminophenoxy)(2-pyridyl))]-N-methylcarboxamide (1 eq) inmethanol was added 4-{[benzylamino]ethyl}benzeneisothiocyanate (1 eq)and heated to 60° C. for 3 h. Preparative chromatography yieldedN-methyl(4-{1-methyl-2-2-[(4-{[benzylamino]ethyl}phenyl)amino)benzimidazol-5-yloxy)-(2-pyridyl))carboxamide.MS: MH⁺=506.

Example 634 Step 1. Synthesis of (5-fluoro-2-nitrophenyl)methylamine

A solution of 5-fluoro-2-nitrophenylamine (1 eq) in methylenechloridewas treated with trifluoroacetic anhydride (1 eq) and stirred for 10minutes at 0° C. The mixture was quenched with saturated sodiumbicarbonate solution. The organic layer was separated and washed withwater, brine, dried and evaporated. To the solution of thetrifluoroacetamide (1 eq) in a mixture of toluene, acetonitrile andsodium hydroxide solution (50%) was added benzyltrimethylammoniumchloride (1 eq) and dimethyl sulfate (1.2 eq). The biphasic mixture wasstirred overnight at room temperature and evaporated. The mixture wastaken up in ethyl acetate, washed with water, brine, dried andevaporated. The crude was purified by column chromatography eluting with1:1 hexanes and ethyl acetate to afford(5-fluoro-2-nitrophenyl)methylamine. MS: MH⁺=170.

Step 2. Synthesis of{4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide

The mixture containing 5-fluoro-2-nitrophenylamine (1 eq), Potassiumbis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2hours at room temperature. To this mixture was added(3-hydroxyphenyl)-N-methylcarboxamide (1 eq) and Potassium carbonate(1.2 eq) and stirred at 90° C. for 16 h. The reaction mixture was thenconcentrated and partitioned between ethyl acetate and water. Theorganic layer was separated and washed with brine, dried, filtered andconcentrated in vacuum to give brown solid. Purification on silica gelgaveN-methyl{4-[3-(methylamino)-4-nitro-phenoxy](2-pyridyl))carboxamide. Itwas taken in methanol and hydrogenated with catalytic amount of 10% Pd/Cto give{4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH⁺=272.

Step 3. Synthesis of(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy)-(2-pyridyl)-N-methylcarboxamide

A solution of the{4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) in methanol was treated with 4-bromophenylisothiocyanate (1 eq) andstirred at 60° C. for 2 hours. The reaction mixture was cooled down toroom temperature and iodomethane (1 eq) was added and stirred overnightat 60° C. The reaction was concentrated and preparative chromatographygave(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy)-(2-pyridyl)-N-methylcarboxamide.MS: MH+=452.

Example 635 Step 1. Synthesis of((5-aminobenzimidazol-2-yl)(4-bromophenylamine)

A solution of the 4-nitrobenzene-1,2-diamine in methanol was treatedwith 4-bromo phenyl isothiocyanate (1 eq) and stirred at 60° C. for 2hours. The reaction mixture was cooled down to room temperature andiodomethane (1 eq) was added and stirred overnight at 60° C. Thereaction was concentrated and purified on silica gel to yield(4-bromophenyl)(5-nitrobenzimidazol-2-yl)amine. The product was taken inmethanol and hydrogenated with catalytic amount of 10% Pd/C to give((5-aminobenzimidazol-2-yl)(4-bromophenylamine). MS: MH⁺=302.

Step 2. Synthesis of[4-({2-[(4-bromophenyl)amino}benzimidazol-5-yl}amino)-(2-pyridyl-N-methylcarboxamide

To a solution of ((5-aminobenzimidazol-2-yl)(4-bromophenylamine (1 eq)in N,N-dimethylformamide was added sodium hydride (2 eq) and the mixturewas microwaved for 8 mins at 220° C. The reaction mixture waspartitioned between ethyl acetate and water and the organic layer wasdried with sodium sulfate and concentrated. Preparative chromatographyyielded[4-({2-[(4-bromophenyl)amino}benzimidazol-5-yl}amino)(2-pyridyl_-N-methylcarboxamide.MS: MH⁺=437.

Example 636 Step 1. Synthesis of(4-{2-[(4-bromophenyl)methyl]-1-methylbenzimidazol-5-yloxy)-(2-pyridyl))-N-methylcarboxamide

To 4-bromophenyl acetic acid (1 eq) in dichoromethane containing a dropof N,N-dimethyl formamide at 0° C. was added oxalyl chloride (1.2 eq).The resulting mixture was then brought to ambient temperature andstirred for 2 h. The mixture was concentrated and to it was addedtetrahydrofuran and[4-(3,4-diaminophenoxy)(2-pyridyl)]-N-methylcarboxamide (1 eq) andtriethyl amine (1 eq) and stirred for 2 h. Formation of the N-acylatedproduct was followed by LC/MS. The mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer was driedwith sodium sulfate and concentrated and taken in acetic acid and heatedto 60° C. for 2 h. Preparative chromatography yielded(4-{2-[(4-bromophenyl)methyl]-1-methylbenzimidazol-5-yloxy)-(2-pyridyl))-N-methylcarboxamide.MS: MH⁺=451.

Example 637 Step 1. Synthesis of4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoicacid

To {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide(1 eq) in methanol was added 4-isothiocyanatobenzoic acid (1 eq) andstirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) andheated to 60° C. for 3 h. and concentrated the solvent and purified onsilica gel to yield4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoicacid. MS: MH⁺=417.

Step 2. Synthesis ofN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]-amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamideCHIR-164277

To4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}-amino)benzoicacid (1 eq) in tetrahydrofuran was added morpholine (2 eq) andN,N-diisopropylethylamine (4 eq) and HBTU (2 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was washed with brineand dried with sodium sulfate. Preparative chromatography gaveN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]-amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide.MS: MH⁺=529.

Example 638 Step 1. Synthesis of3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoicacid

To 4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) in methanol was added 3-isothiocyanatobenzoic acid (1 eq) andstirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) andheated to 60° C. for 3 h and concentrated the solvent and purified onsilica gel to yield3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoicacid. MS: MH+=417.

Step 2. Synthesis ofN-methyl[3-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]-amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide

To3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}-amino)benzoicacid (1 eq) in tetrahydrofuran was added morpholine (2 eq) andN,N-diisopropylethylamine (4 eq), EDCI (2 eq), HOAT (1.2 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried with sodium sulfate. Preparativechromatography gaveN-methyl[3-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)-phenyl]amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide.MS: MH+=529.

Each of the compounds 639-698, listed in Table 7 were synthesized asindicated in the right hand column by the method described in one of theExamples 627-638 or as otherwise indicated.

TABLE 7 Synthesis as in Example Structure Name MH+ Example: 639

4-({2-[(4-bromophenyl)- methyl]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 452.3 636 640

4-({2-[(4-bromophenyl)- amino]-1H-benzimidazol-6-yl}amino)-N-methylpyridine- 2-carboxamide 438.3 635 641

4-({2-[(4-bromophenyl)- amino]-1-methyl-1H- benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 453.3 634 642

N-methyl-4-({1-methyl-2- [(4-{1-[(phenylmethyl)-amino]ethyl}phenyl)amino]- 1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 507.6 633 643

4-({2-[(4-{[2-(dimethyl- amino)ethyl]oxy}phenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 461.5 631 644

N-methyl-4-{[1-methyl-2- ({4-[(methylamino)- carbonyl]phenyl }amino)-1H-benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 431.5 637 645

N-methyl-4-({1-methyl-2- [(4-{[(2-morpholin-4-yl- ethyl)amino]carbonyl}-phenyl)amino]-1H- benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 530.6637 646

4-{[2-({4-[(4-ethylpiperazin- 1-yl)carbonyl]phenyl}- amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 514.6 637 647

N-methyl-4-({1-methyl-2- [(4-{[(2-pyridin-4-ylethyl)-amino]carbonyl}phenyl)amino]- 1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide 522.6 637 648

4-[(2-{[4-({[2-(dimethyl- amino)ethyl]amino}- carbonyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 488.6637 649

4-({2-[(4-{[3-(dimethyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 514.6 637 650

N-methyl-4-({1-methyl-2- [(4-{[(1-methylethyl)amino]-carbonyl}phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 459.5 637 651

4-[(2-{[4-(2,6-dimethyl- morpholin-4-yl)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 487.6  120a 652

N-methyl-4-({1-methyl-2- [(4-piperidin-1-ylphenyl)-amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 457.5  120a 653

N-methyl-4-[(1-methyl-2- {[4-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}carbonyl)- phenyl]amino}-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 528.6 637 654

N-methyl-4-({1-methyl-2- [(4-{[(2-piperidin-1-ylethyl)-amino]carbonyl}phenyl)amino]- 1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide 528.6 637 655

4-[(2-{[4-({[3-(1H-imidazol- 1-yl)propyl]amino}carbonyl)-phenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 525.6 637 656

4-[(2-{[4-({[(1-ethyl- pyrrolidin-2-yl)methyl]- amino}carbonyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 528.6 637 657

N-methyl-4-({1-methyl-2- [(4-{[(2-pyrrolidin-1-yl-ethyl)amino]carbonyl}- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 514.6 637 658

N-methyl-4-({1-methyl-2- [(4-{[(pyridin-4-ylmethyl)-amino]carbonyl}phenyl)- amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 508.6 637 659

N-methyl-4-{[1-methyl-2- ({4-[(1,3-thiazol-2-yl-amino)carbonyl]phenyl}amino)- 1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide 500.6 637 660

N-methyl-4-[(1-methyl-2- {[4-({[3-(4-methylpiperazin-1-yl)propyl]amino}carbonyl)- phenyl]amino}-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 557.7 637 661

4-{[2-({4-[(1-aza- bicyclo[2.2.2]oct-3-ylamino)-carbonyl]phenyl}amino)-1- methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2- carboxamide 526.6 637 662

4-({2-[(4-{[(3S)-1- azabicyclo[2.2.2]oct-3- ylamino]carbonyl}phenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 526.6 637 663

N-methyl-4-{[1-methyl-2- ({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)- 1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide 500.6 637 664

N-methyl-4-{[1-methyl-2- ({4-[(4-methyl-1,4-diazepan-1-yl)carbonyl]phenyl}- amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide 514.6 637 665

N-methyl-4-[(1-methyl-2- {[4-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}carbonyl) phenyl]amino}-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 542.6 637 666

4-({2-[(4-{[(3R)-3-hydroxy- pyrrolidin-1-yl]carbonyl}-phenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 487.5 637 667

4-({2-[(4-{[(3S)-3-hydroxy- pyrrolidin-1-yl]carbonyl}-phenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 487.5 637 668

4-({2-[(4-{[4-(2-hydroxy- ethyl)piperazin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 530.6 637 669

4-{[2-({4-[(4-acetylpiperazin- 1-yl)carbonyl]phenyl}-amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 528.6 637 670

4-({2-[(4-{[(3R)-3-(dimethyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 514.6 637 671

4-({2-[(4-{[(3S)-3-(dimethyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 514.6 637 672

N-methyl-4-({1-methyl-2- [(4-{[(tetrahydrofuran-2-ylmethyl)amino]carbonyl}- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 501.6 637 673

4-({2-[(4-{[(3R)-3-(acetyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 528.6 637 674

4-[(2-{[4-(1,4′-bipiperidin-1′- ylcarbonyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 568.7637 675

N-methyl-4-[(1-methyl-2- {[4-(morpholin-4-yl- carbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 487.5 637 676

4-({2-[(4-{[(3R,5S)-3,5- dimethylpiperazin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 514.6 637 677

N-methyl-4-[(1-methyl-2- {[4-(pyrrolidin-1-yl-carbonyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 471.5 637 678

4-({2-[(4-{[(2R)-2-(amino- carbonyl)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 514.6 637 679

N-methyl-4-({1-methyl-2- [(4-{[4-(1-methylethyl)-piperazin-1-yl]carbonyl}- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 528.6 637 680

4-[(2-{[4-({(2R,5S)-2- [(dimethylamino)methyl]-5- methylmorpholin-4-yl}-carbonyl)phenyl]amino}-1- methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 558.7 637 681

N-methyl-4-({1-methyl-2- [(4-{[(1-methylpiperidin-4-yl)amino]carbonyl}phenyl) amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 514.6 637 682

4-[(2-{[4-({2-[(di- methylamino)methyl] morpholin-4-yl}carbonyl)-phenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 544.6 637 683

4-{[2-({4-[(4-ethylpiperazin- 1-yl)methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide500.6 630 684

N-methyl-4-{[1-methyl-2- ({4-[methyl(1-methyl- pyrrolidin-3-yl)amino]-phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 486.6631 685

4-{[2-({4-[[2-(dimethyl- amino)ethyl](methyl)amino]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 474.6 631 686

4-[(2-{[4-(4-ethylpiperazin-1- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-methylpyridine-2-carboxamide 486.6 631 687

4-{[2-({4-[2-(4- ethylpiperazin-1- yl)ethyl]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 514.6632 688

N-methyl-4-[(1-methyl-2- {[4-(2-morpholin-4- ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy] pyridine-2-carboxamide 487.6 632 689

N-methyl-4-[(1-methyl-2- {[4-(2-piperidin-1- ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy] pyridine-2-carboxamide 485.6 632 690

N-methyl-4-[(1-methyl-2-{4- [(4-methylpiperazin-1- yl)methyl]phenyl}-1H-benzimidazol-5-yl)oxy] pyridine-2-carboxamide 471.6 628 691

N-methyl-4-({1-methyl-2- [({4-[(4-methylpiperazin-1-yl)methyl]phenyl}carbonyl) amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 514.6 627 692

N-methyl-4-{[1-methyl-2- ({[4-(morpholin-4-ylmethyl)phenyl]carbonyl}amino)- 1H-benzimidazol-5-yl]oxy} pyridine-2-carboxamide501.6 627 693

N-methyl-4-{[1-methyl-2- ({[4-(piperidin-1- ylmethyl)phenyl]carbonyl}amino)-1H-benzimidazol-5- yl]oxy}pyridine-2-carboxamide 499.6 627 694

N-methyl-4-({1-methyl-2-[4- (morpholin-4-ylmethyl)phenyl]-1H-benzimidazol- 5-yl}oxy)pyridine-2-carboxamide 458.5 628 695

N-methyl-4-({1-methyl-2-[4- (piperidin-1-ylmethyl)phenyl]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 456.6 628 696

4-({2-[4-({[2- (dimethylamino)ethyl]amino} methyl)phenyl]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 459.6 628 697

4-{[2-(4-{[[2-(di- methylamino)ethyl](methyl) amino]methyl}phenyl)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 473.6628 698

4-[(4-methylpiperazin-1- yl)methyl]-N-{5-[(4-pyridin-3-ylpyrimidin-2-yl)oxy]-1H- benzimidazol-2-yl}benzamide 521.6 629

Example 699 Step 1. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

To a stirred solution of concentrated nitric acid (22 eq) was added 2h-benzo[d]1,3-dioxolane (1 eq) at 0-10° C. for 0.5 h and stirred foranother 0.5 h. To this reaction mixture was then added concentratedsulfuric acid (0.06 eq) drop-wise at 0-10 C.° for 0.5 h and stirred at20 C.° for 0.5 h. It was then poured on to crushed ice, and theseparated solid was filtered washed with water and dried to give5,6-dinitro-2 h-benzo[d]1,3-dioxalane. MS: MH⁺ 212

Step 2. Synthesis of methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl)amine

To a stirred solution of methyl amine in ether and ethanol (1.5:1) wasadded 5,6-dinitro-2 h-benzo[d]1,3-dioxalane and stirred at ambienttemperature for 24 h. The solvent was evaporated under vacuum and thesolid was washed with water and dried to give methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxan-5-yl))amine. MS: MH⁺ 196

Step 3. Synthesis of 2-methoxy-4-(methylamino)-5-nitrophenol

To a stirred solution of methanol was added sodium metal (4.8 eq) slowlyat ambient temperature followed by methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl))amine (1 eq) and stirred for 2 h. Themixture was then refluxed for 0.5 h and diluted with water. Aftercooling it to ambient temperature the separated solid was filtered anddried to give 2-methoxy-4-(methylamino)-5-nitrophenol as a red solid.MS: MH+ 198

Step 4. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq)in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) andcontinued stirring at ambient temperature utility solidified. To it wasthen added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrouspotassium carbonate (1 eq) and the resulting mixture was heated to 50°C. whereby the solid liquified. It was then heated to 110° C. for 12 h.After cooling to ambient temperature the solvent was distilled off andthe resulting solid was extracted using ethyl acetate in a soxhletapparatus for 48 h. the organic layer was cooled to 0° C., when theproduct crystallized from the ethyl acetate to give{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide.MS: MH+ 332

Step 5. Synthesis of4-{2-[(4-chlorophenyl)amino]-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

Totert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate(1 eq) in methanol was added 4-chlorobenzeneisothiocyanate (1 eq) andstir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-chlorophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-chlorophenylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH+=424.

Step 6. Synthesis of[4-(2-{[4-chlorophenyl)amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

To4-(2-{[4-chloropheylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[4-chlorophenyl]amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH+=522.

Example 700 Step 1. Synthesis of4-{2-[(4-bromo-3-methylphenyl)amino]-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

Totert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate(1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1eq) and stir at ambient temperature for 16 h. Formation of thecorresponding thiourea was followed by LC/MS. To it was then addediodomethane (1 eq) and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-bromo-3-methylphenyl]amino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH+=482.

Step 2. Synthesis of[4-(2-{[4-bromo-3-methylphenyl)amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

To4-(2-{[4-bromo-3-methylpheylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[4-bromo-3-methylphenyl]amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH+=579.

Example 701 Step 1. Synthesis of4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylicacid

To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 3-isopropylbenzeneisothiocyanate (1 eq) andstir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation of4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-bromo-3-methylphenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH+=437

Step 2. Synthesis of4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid)2-pyrrolidin-1-yl-ethyl)-amide

To4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), EDCI (2 eq), HOAT (1.2 eq) and N,N-diisopropylethylamine (4 eq) andstir at ambient temperature for 16 h. The mixture was then concentratedand partitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid)2-pyrrolidin-1-yl-ethyl)-amide. MS: MH+=499.

Example 702 Step 1. Synthesis of3-chloro-4-(2-methyl-5-nitrophenyl)pyridine

Nitrogen was bubbled through a solution of2-bromo-1-methyl-4-nitrobenzene (1 eq) in dimethoxyethane and water(3:1) for 0.5 h. Bis(diphenylphosphino)ferrocene Palladium(II)chloride(0.05 eq) followed by 3-chloro-4-pyridine boronic acid hydrate (1 eq)and sodium carbonate (3 eq) was added and the mixture was heated to 90°C. for 16 h under nitrogen. The reaction mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried with sodium sulfate and concentrated.Purification on silica gel gave3-chloro-4-(2-methyl-5-nitrophenyl)pyridine. MS: MH+=248.

Note: The same procedure was used for Suzuki reaction between thehalopyridines and the nitrophenylboronic acids.

Boronic acids were synthesized using the following procedure ifcommercially unavailable.

Step 1a. Synthesis of 2-fluoropyridine boronic acid

A flame-dried flask was charged with toluene and tetrahydrofuran (4:1)and then with 4-bromo-2-fluoropyridine (1 eq) and triisopropylborate(1.2 eq) and the flask was cooled to −70° C. Then n-butyllithium (1.2eq) was added dropwise over 0.5 h and the mixture was stirred for 0.5 hat −70° C. The reaction mixture was then brought to −20° C. and 2Nhydrochloric acid was added to it. Formation of 2-fluoropyridine boronicacid was seen by LC/MS on warming the mixture to ambient temperature.The mixture was partitioned between ethyl acetate and water. The organiclayer was dried with sodium sulfate and concentrated to yield2-fluoropyridine boronic acid. MS: MH+=141.

Step 2. Synthesis of 3-(3-chloro(4-pyridyl)-4-methylphenylamine

To the mixture containing 3-chloro-4-(2-methyl-5-nitrophenyl)pyridine inacetic acid was added Fe dust (5 eq) and the resulting mixture wasstirred at ambient temperature for 6 h. To it was then added saturatedsodium carbonate to bring it to neutral pH and extracted with ethylacetate. The organic layer was washed with brine and dried with sodiumsulfate and concentrated and passed through a plug of silica to yield3-(3-chloro(4-pyridyl))-4-methylphenylamine. MS: MH+=218.

Step 3. Synthesis of3-(3-chloro(4-pyridyl))-4-methylbenzeneisothiocyanate

To 3-(3-chloro(4-pyridyl))-4-methylphenylamine in acetone at 0° C. wasadded sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield3-(3-chloro(4-pyridyl))-4-methylbenzeneisothiocyanate. MS: MH+=260.

Step 4. Synthesis of{4-(2-{[3-(3-chloro(4-pyridyl))-4-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

To 3-(3-chloro(4-pyridyl))-4-methylbenzeneisothiocyanate (1 eq) inmethanol was added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and the resulting mixture was stirred at ambient temperature for 16h. LC/MS shows formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to neutral pH with 1N sodium hydroxide. It was thenextracted with ethyl acetate and the organic layer was washed with brineand dried with sodium sulfate. The crude was then titrated with hotmethanol to yield{4-(2-{[3-(3-chloro(4-pyridyl))-4-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH+=498.

Example 703 1. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

To a stirred solution of concentrated nitric acid (22 eq) was added 2h-benzo[d]1,3-dioxolane (1 eq) at 0-10° C. for 0.5 h and stirred foranother 0.5 h. To this reaction mixture was then added concentratedsulfuric acid (0.06 eq) drop-wise at 0-10 C.° for 0.5 h and stirred at20 C.° for 0.5 h. It was then poured on to crushed ice, and theseparated solid was filtered washed with water and dried to give5,6-dinitro-2 h-benzol[d]1,3-dioxalane. MS: MH+ 212

Step 2. Synthesis of methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl)amine

To a stirred solution of methyl amine in ether and ethanol (1.5:1) wasadded 5,6-dinitro-2 h-benzol[d]1,3-dioxalane and stirred at ambienttemperature for 24 h. The solvent was evaporated under vacuum and thesolid was washed with water and dried to give methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxan-5-yl))amine. MS: MH+ 196

Step 3. Synthesis of 2-methoxy-4-(methylamino)-5-nitrophenol

To a stirred solution of methanol was added sodium metal (4.8 eq) slowlyat ambient temperature followed by methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl))amine (1 eq) and stirred for 2 h. Themixture was then refluxed for 0.5 h and diluted with water. Aftercooling it to ambient temperature the separated solid was filtered anddried to give 2-methoxy-4-(methylamino)-5-nitrophenol as a red solid.MS: MH+ 198

Step 4. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq)in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) andcontinued stirring at ambient temperature utility solidified. To it wasthen added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrouspotassium carbonate (1 eq) and the resulting mixture was heated to 50°C. whereby the solid liquified. It was then heated to 110° C. for 12 h.After cooling to ambient temperature the solvent was distilled off andthe resulting solid was extracted using ethyl acetate in a soxhletapparatus for 48 h. The organic layer was cooled to 0° C., when theproduct crystallized from the ethyl acetate to give{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide.MS: MH+ 332

Step 5. Synthesis of{4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide

A solution of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide.In methanol was hydrogenated with 10% Pd/C. The catalyst was filteredoff and the solvent was concentrated to yield{4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide.MS: MH+: 302.

Step 6. Synthesis of(4-{2-[(4-bromo-3-methylphenyl)amino)]-6-methoxy-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide

To a solution of{4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide(1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1eq) and stirred at 60° C. for 2 h. Formation of thiourea was followed byLC/MS. To it was added iodomethane (1 eq) and heated to 60° C. for 3 h.The mixture was concentrated and purified on preparative chromatographyto yield(4-{2-[(4-bromo-3-methylphenyl)amino)]-6-methoxy-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide.MS: MH+=496.

Example 704 Synthesis of(5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide

Step 1. Synthesis of methyl-5-(4-nitrophenoxy)pyridine-3-carboxylate

The mixture containing methyl-5-hydroxypyridine-3-carboxylate (1 eq),Potassium bis(trimethylsilyl)amide (1.2 eq) was stirred inN,N-dimethylformamide for 2 hours at room temperature. To this mixturewas added 1-fluoro-4-nitrobenzene (1.1 eq) and Potassium carbonate (1.2eq) and stirred at 80° C. for 16 h. The reaction mixture was thenconcentrated and partitioned between ethyl acetate and water. Theorganic layer was separated and washed with brine, dried, filtered andconcentrated in vacuum to give brown solid. Purification on silica gelmethyl-5-(4-nitrophenoxy)pyridine-3-carboxylate. MS: MH+=274.

Step 2. Synthesis of methyl5-[4-aminophenoxy]pyridine-3-carboxylate

The mixture containing methyl-5-(4-nitrophenoxy)pyridine-3-carboxylatein methanol with catalytic amount of 10% Pd/C was hydrogenated to yieldmethyl5-[4-aminophenoxy]pyridine-3-carboxylate. MS: MH+=244.

Step 3. Synthesis ofmethyl-5-[4-(2,2,2-trifluoroacetamino)phenoxy]pyridine-3-carboxylate

A solution of methyl-5-[4-aminophenoxy]pyridine-3-carboxylate (1 eq) inmethylene chloride was treated with trifluoroacetic anhydride (1 eq) andstirred for 10 minutes at 0° C. The mixture was quenched with saturatedsodium bicarbonate solution. The organic layer was separated and washedwith water, brine, dried and evaporated to yieldmethyl-5-[4-(2,2,2-trifluoroacetamino)phenoxy]pyridine-3-carboxylate.MS: MH+=340.

Step 4. Synthesis ofmethyl-5-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]-pyridine-3-carboxylate

To a solution ofmethyl-5-[4-(2,2,2-trifluoroacetamino)phenoxy]pyridine-3-carboxylate inacetic acid and acetic anhydride (1:1) at 0° C. was added nitric acidfollowed by sulfuric acid. Followed the reaction by LC and once completeit was partitioned between ethyl acetate. The organic layer was washedwith brine and dried with sodium sulfate and concentrated to yieldmethyl5-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]-pyridine-3-carboxylate.MS: MH+=385.

Step 5. Synthesis ofmethyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-3-carboxylate

To the solution of themethyl5-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]-pyridine-3-carboxylate(1 eq) in a mixture of toluene, acetonitrile and sodium hydroxidesolution (50%) was added benzyltrimethylammonium chloride (1 eq) anddimethyl sulfate (1.2 eq). The biphasic mixture was stirred overnight atroom temperature and evaporated. The mixture was taken up in ethylacetate, washed with water, brine, dried and evaporated. The crude waspurified by column chromatography to affordmethyl-4-[4-(methylamino)-3-nitrophenoxy]pyridine-3-carboxylate. MS:MH+=303.

Step 6. Synthesis ofmethyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate

The mixture containingmethyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-3-carboxylate washydrogenated with 10% Pd/C to yieldmethyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate. MS:MH+=273.

Step 7. Synthesis ofmethyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate

A solution of themethyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate (1 eq) inmethanol (8 ml) was treated with 4-bromophenylisothiocyanate (1 eq) andstirred at 60° C.-65° C. for 2 hours. The reaction mixture was cooleddown to room temperature and methyl iodide (1 eq) was added and stirredovernight at 60° C. The reaction was cooled down to room temperature,evaporated, taken up in ethyl acetate and washed with water and brine,dried, evaporated under reduced pressure. Column chromatography yieldedmethyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate.MS: MH+=452

Step 8. Synthesis of(5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide

To a solution ofmethyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylatein added methylamine and the resulting mixture was stirred at ambienttemperature for 16 h. It was then concentrated and purified bypreparative chromatography to yield(5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide.MS: MH+=452.

Each of the compounds 705-746, listed in Table 8 were synthesized asindicated in the right hand column by the method described in one of theExamples 699 or 700.

TABLE 8 Ex- Synthe- am- sized as in ple Molecular Structure Name MH+Example: 705

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [(1-ethyl-pyrrolidin-2- yl)methyl]-pyridine-2-carboxamide 594.5 700 706

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (2-morpholin-4-ylethyl) pyridine-2-carboxamide596.5 700 707

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [3-(4-methyl-piperazin-1-yl)propyl]pyridine-2- carboxamide 623.6 700 708

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- 1,3-thiazol-2-ylpyridine-2- carboxamide 566.5700 709

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [2-(1-methyl-pyrrolidin-2-yl)ethyl]pyridine-2- carboxamide 594.5 700 710

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide 580.5 700 711

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [3-(1H-imidazol-1-yl) propyl]pyridine-2-carboxamide 591.5 700 712

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [2-(methyloxy)-ethyl] pyridine-2-carboxamide541.4 700 713

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (2-hydroxyethyl)-pyridine- 2-carboxamide 527.4700 714

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (2-piperidin-1-ylethyl) pyridine-2-carboxamide594.5 700 715

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (3-piperidin-1-ylpropyl)pyridine-2-carboxamide 608.5 700 716

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [3-(4-methyl-piperazin-1-yl)propyl]pyridine-2- carboxamide 623.6 700 717

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (2-pyridin-4-yl-ethyl) pyridine-2-carboxamide588.5 700 718

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (2-piperazin-1-yl-ethyl)pyridine-2-carboxamide 595.5 700 719

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [3-(methyloxy)-propyl] pyridine-2-carboxamide555.4 700 720

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- propylpyridine-2- carboxamide 525.4 700 721

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- ethylpyridine-2- carboxamide 511.4 700 722

N-[2-(acetylamino)ethyl]- 4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6- (methyloxy)-1H- benzimidazol-5-yl]oxy}pyridine-2-carboxamide 568.4 700 723

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [2-(2-oxo-imidazolidin-1-yl)ethyl]-pyridine-2- carboxamide 595.5 700 724

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [3-(2-oxo-pyrrolidin-1-yl) propyl]-pyridine-2-carboxamide 608.5 700 725

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-[(1-ethyl- pyrrolidin-2-yl)methyl]pyridine-2-carboxamide 536.0 699 726

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-(2-morpholin- 4-yl-ethyl)pyridine-2-carboxamide 538.0 699 727

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-[3-(4-methyl- piperazin-1-yl)propyl]pyridine-2-carboxamide 565.1 699 728

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-1,3-thiazol-2-yl-pyridine-2-carboxamide 508.0 699 729

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]oxy}-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]pyridine-2-carboxamide 536.0 699 730

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-(2-pyrrolidin- 1-yl-ethyl)pyridine-2-carboxamide 522.0 699 731

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-[2-(dimethyl-amino)-ethyl]pyridine-2- carboxamide 496.0 699 732

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-[3-(1H- imidazol-1-yl)-propyl]pyridine-2-carboxamide 533.0 699 733

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-[2-(methyloxy) ethyl]-pyridine-2-carboxamide 482.9 699 734

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-(2-hydroxy- ethyl)-pyridine-2-carboxamide 468.9 699 735

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-(2-piperidin- 1-ylethyl)pyridine-2-carboxamide 536.0 699 736

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-(3-piperidin- 1-yl-propyl)pyridine-2-carboxamide 550.1 699 737

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-(3-pyrrolidin-1-yl-propyl)pyridine-2- carboxamide 536.0 699 738

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]-oxy}-N-(2-pyridin-4- ylethyl)-pyridine-2-carboxamide 530.0 699 739

4-{[2-[(4-chlorophenyl)]-1- methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- (2-piperazin-1-ylethyl) pyridine-2-carboxamide537.0 699 740

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [3-(methyloxy)-propyl] pyridine-2-carboxamide497.0 699 741

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]-oxy}- N-propylpyridine-2- carboxamide 466.9 699 742

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]-oxy}- N-ethylpyridine-2- carboxamide 452.9 699 743

N-[2-(acetylamino)ethyl]-4- {[2-[(4-chlorophenyl) amino]-1-methyl-6-(methyloxy)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 510.0 699744

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}-N- [2-(2-oxo- imidazolidin-1-yl)ethyl]-pyridine-2-carboxamide 537.0 699 745

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]-oxy}- N-[(3R)-pyrrolidin-3- yl]pyridine-2-carboxamide494.0 699 746

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]-oxy}- N-[3-(2-oxopyrrolidin-1- yl)propyl]pyridine-2-carboxamide 550.0 699

Each of the compounds 747-782, listed in the below table weresynthesized as indicated in the right hand column by the methoddescribed in one of the Examples 702 or 703 unless indicated otherwise.

TABLE 9 Ex- Synthe- am- sized as in ple Structure Name MH+ Example: 747

4-{[2-[(4-chlorophenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 438.9 703 748

4-{[2-[(3-chlorophenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 438.9 703 749

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide497.4 703 750

N-methyl-4-({1-methyl-6- (methyloxy)-2-[(4-methyl- phenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 418.5 703 751

4-{[2-(2,3-dihydro-1H-inden-5- ylamino)-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 444.5703 752

N-methyl-4-{[1-methyl-6- (methyloxy)-2-(pyridin-3-yl-amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 405.4 703 753

4-{[2-{[4-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide460.5 703 754

4-{[2-[(2,5-dichlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 473.3703 755

4-{[2-(1,3-benzodioxol-5- ylamino)-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 448.4703 756

4-{[2-[(3-chloro-2-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide452.9 703 757

4-{[2-[(4-ethylphenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 432.5 703 758

4-{[2-[(4-bromophenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 483.3 703 759

N-methyl-4-{[1-methyl-6- (methyloxy)-2-({4-[(trifluoro-methyl)oxy]phenyl}amino)-1H- benzimidazol-5-yl]oxy}-pyridine-2-carboxamide 488.4 703 760

4-{[2-[(2,4-dimethylphenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 432.5703 761

N-methyl-4-(3-{[1-methyl-5- ({2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-1H- benzimidazol-2-yl]amino}-phenyl)pyridine-2-carboxamide 508.6 703 762

4-[(2-{[3-(3-chloropyridin-4- yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 500.0702 763

4-[(2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 469.5 702 764

N-methyl-4-[(1-methyl-2-{[3- (1-methylpiperidin-4-yl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 471.6702 765

4-[(2-{[3-(2-fluoropyridin-4- yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 483.5702 766

N-methyl-4-{[1-methyl-2-({3- [3-(trifluoromethyl)pyridin-4-yl]phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide519.5 702 767

N-methyl-4-[(1-methyl-2-{[3- (2-methylpyridin-4-yl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 465.5 702 768

N-methyl-4-[(1-methyl-2-{[3- (4-methylpiperazin-1-yl)phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide472.6 702 769

4-[(2-{[4-chloro-3-(4-methyl- piperazin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide507.0 702 770

4-[(2-{[3-(3-chloropyridin-4- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 485.9 702 771

4-[(2-{[3-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 417.5 702 772

4-{[2-({3-(3-chloropyridin-4- yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 569.9 702 773

N-methyl-4-[(1-methyl-6- (methyloxy)-2-{[3-(2-methyl-pyridin-4-yl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 495.6 702 774

N-methyl-4-{[1-methyl-6- (methyloxy)-2-({3-[3-(trifluoro-methyl)pyridin-4-yl]phenyl}- amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide 549.5 702 775

4-{[2-{[3-(3-chloropyridin-4- yl)-4-methylphenyl]amino}-1-methyl-6-(methyloxy)-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 530.0 702 776

4-{[2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide499.5 702 777

4-[(2-{[3-(dimethylamino)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 431.51 778

N-methyl-4-({1-methyl-2-[(3- pyrimidin-5-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 452.5 702 779

4-{[2-({3-(2-fluoropyridin-4- yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 553.5 702 780

4-{[2-({3-(3-fluoropyridin-4- yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 553.5 702 781

N-methyl-4-({1-methyl-2-[(3- thien-2-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 456.5 702 782

N-methyl-4-({1-methyl-2-[(3- quinolin-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 501.6 702

Example 783 Synthesis of[4-(2-{[6-(dimethylamino)(3-pyridyl)]amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

Step 1. Synthesis of 2-(Dimethylamino-5-nitropyridine

2-Chloro-5-nitropyridine (1.0 eq) and dimethylamine (2 M in EtOH, 4.6eq) in NMP were heated for 2 h at 100° C. The solution was then pouredslowly into H²O. The filtrate that formed was filtered and dried to give2-(dimethylamino)-5-nitropyridine.

Step 2. Synthesis of 2-(Dimethylamino-5-aminopyridine

A mixture of 2-(dimethylamino)-5-nitropyridine (1 eq) and 5% palladiumon carbon (0.3 eq) in ethanol was stirred at room temperature andflushed with nitrogen. The reaction vessel was evacuated and purged withhydrogen three times. The reaction mixture was left under an atmosphereof hydrogen overnight. Nitrogen was flushed through the reaction andthen the reaction was filtered through a celite pad. The celite pad waswashed with excess ethanol before the solvent was removed by evaporationunder reduced pressure to afford 2-(dimethylamino)-5-aminopyridine.

Step 3. Synthesis of 2-(Dimethylamino)-5-isothiocyanate pyridine

2-(Dimethylamino)-5-aminopyridine (1.0 eq) was taken up in acetone andcooled to 0 C. Thiophosgene (1.6 eq) was added dropwise and the reactionwas stirred for 30 minutes at 0 C before the excess thiophosgene andacetone were removed by evaporation under reduced pressure.

Step 4. Synthesis of[4-(2-{[6-(dimethylamino)(3-pyridyl)]amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

A solution of the{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1.1eq) in methanol was treated with 2-(dimethylamino)-5-isothiocyanatepyridine (1.0 eq) and stirred at 60° C. for 2 hours. Methyl iodide (1eq) was added and stirred overnight at 60° C. The reaction was cooleddown to room temperature, evaporated and purified by reverse phase HPLC.MS: MH+=418.3

Example 784

A solution of 1 (1 eq) and 10% palladium on carbon (0.1 eq) in ethylacetate was stirred at room temperature and flushed with nitrogen.Hydrogen was flushed through the reaction for 2-3 hours or until thereaction was determined to be complete by HPLC. Nitrogen was flushedthrough the reaction for 15 minutes before the reaction was filteredthrough a celite pad. The celite pad was washed with excess ethylacetate and methylene chloride before the combined organic solution wasremoved by evaporation under reduced pressure to afford the product as asolid 2. MS: MH+=207

A solution of 2 (1 eq) and sodium carbonate (1.5 eq) in acetone wasstirred under nitrogen in an ice bath. Thiophosgene (1.5 eq) was addeddrop wise over 30 minutes. The reaction was stirred for another 30minutes in the ice bath before being removed and allowed to warm to RT.The reaction was stirred at RT for 1.5 h before the reaction solutionwas concentrated under vacuum. Toluene was added to the crude productand removed under vacuum to azeotrope off any residual thiophosgene andafford the product 3. MS: MH+=249

A solution of 3 (1.0 eq) and 4 (1.0 eq) in MeOH was stirred at RTovernight. Ferric chloride (1.2 eq) was added and the resulting reactionmixture was stirred overnight at RT. The reaction mixture wasconcentrated under vacuum. The crude product was partitioned with EtOAcand water and filtered. The layers were separated and the aqueous phasewas neutralized (pH=7) with saturated Na2CO3 solution. The resultingaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na2SO4), and concentrated to give the desiredproduct 5. MS: MH+=487

A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq) inDME/H²O (3:1) was degassed by bubbling argon through the solution for 10minutes. Pd(II)(dppf)Cl2.MeCl2 (0.1 eq) was added to the reactionsolution and the reaction was sealed. The reaction was heated at 100° C.overnight. The reaction was cooled to RT and ethyl acetate and waterwere added. The organic layer was separated from the aqueous layer. Theaqueous layer was washed once more with ethyl acetate. The organiclayers were combined, dried (Na2SO4), and concentrated under vacuum toyield the desired product 7. MS: MH+=469

The reaction flask was flame dried and cooled under nitrogen. A solutionof 8 (1.0 eq) in THF was added to the reaction flask followed bytriisopropyl borate (1.2 eq). The reaction solution was placed in a dryice/acetone bath to stir at approximately −72° C. N-butyl lithium (1.5eq, 2.5M solution in hexane) was added drop wise over 40 minutes. Thereaction solution was stirred for another 30 minutes in the dryice/acetone bath. The reaction solution was then transferred to asaturated NaCl/dry ice bath to stir at approx. −25° C. and stirred for20 minutes before 2N HCl (2.0 eq) was added. The reaction solution wasthen removed from the bath to stir and warm to RT. The organic andaqueous layers were separated. The aqueous layer was washed once withethyl acetate. The organic layers were combined, dried (Na2SO4), andconcentrated under vacuum to yield the desired product 9. MS: MH+=141

Each of the compounds 785-802, listed in the below table weresynthesized as indicated in the right hand column by the methoddescribed in one of the Examples 783 or 784.

TABLE 10 Synthesized as in Example Structure Name MH⁺ Example: 785

4-({2-[(4-fluoro-3-pyridin-3- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 469.5 784 786

4-({2-[(4-fluoro-3-pyridin-4- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 469.5 784 787

4-({2-[(4-chloro-3-pyridin-4- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 485.9 784 788

4-[(2-{[4-chloro-3-(2- fluoropyridin-4-yl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 503.9 784 789

4-({2-[(4-chloro-3-pyridin-2- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 485.9 784 790

4-({2-[(4-chloro-3-pyridin-3- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 485.9 784 791

4-[(2-{[4-chloro-3-(3- fluoropyridin-4-yl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 503.9 784 792

4-[(2-{[4-chloro-3-(6- fluoropyridin-3-yl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 503.9 784 793

4-{[2-({4-chloro-3-[6- (methyloxy)pyridin-3-yl]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 516 784 794

4-[(2-{[3-(6-fluoropyridin-3-yl)- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 537.5 784 795

4-[(2-{[3-(3-fluoropyridin-4-yl)- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 537.5 784 796

4-[(2-{[3-(2-fluoropyridin-4-yl)- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 537.5 784 797

N-methyl-4-[(1-methyl-2-{[3- [6-(methyloxy)pyridin-3-yl]-5-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 549.5 784 798

N-methyl-4-[(1-methyl-2-{[3- pyridin-2-yl-5-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 519.5784 799

N-methyl-4-[(1-methyl-2-{[3- pyridin-3-yl-5-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 519.5784 800

N-methyl-4-[(1-methyl-2-{[3- pyridin-4-yl-5-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 519.5784 801

4-[(2-{[6-(dimethylamino)- pyridin-3-yl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 418.5 783 802

N-methyl-4-({1-methyl-2-[(6- pyrrolidin-1-ylpyridin-3-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 444.5 783

Example 803

Step 1.4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (2-phenylmethanesulfonylamino-ethyl)-amide

To a mixture containing4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (2-amino-ethyl)-amide (1 eq) (prepared using previously describedexample 3), K2CO3 (5 eq), (0.2 M in a 5:1 mixture of acetonitrile andwater) were added α-toluenesulfonyl chloride (1 eq) via syringe. Theresulting heterogeneous mixture was allowed to stir for 1 hour at roomtemperature. The mixture was then diluted with water and extracted withdichloromethane. The organics were washed with water and a saturatedsolution of sodium chloride, dried with sodium sulfate and concentratedin vacuo to viscous oil. Purification by chromatography yielded4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (2-phenylmethanesulfonylamino-ethyl)-amide. MS: MH+ 599

The compounds shown in the following Table (Examples 804-812) wereprepared from following the procedure described for Example 803.

TABLE 11 Exam- ple Structure Name MH+ 804

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- methylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 523.6 805

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- {[(phenylmethyl)sulfonyl]-amino}ethyl)pyridine-2- carboxamide 599.7 806

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- {[(trifluoromethyl)sulfonyl]-amino}ethyl)pyridine-2- carboxamide 577.6 807

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- [(phenylsulfonyl)amino]ethyl}-pyridine-2-carboxamide 585.7 808

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- [(propylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 551.7 809

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- {[(4-methylphenyl)sulfonyl]-amino}ethyl)pyridine-2- carboxamide 599.7 810

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- [(thien-2-ylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 591.7 811

N-(2-{[(1-methylethyl)- sulfonyl]amino}ethyl)-4-[(1-methyl-2-{[3-(1-methylethyl)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2- carboxamide 551.7 812

N-(2-{[(5-chlorothien-2-yl)- sulfonyl]amino}ethyl)-4-[(1-methyl-2-{[3-(1-methylethyl)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2- carboxamide 626.2

Example 813

Step 1. 4-{2-(3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-phenylamino]-1-methyl-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylic acidmethyl amide

To a mixture of4-[2-(3-Ethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide (1 eq) (prepared using previously described example 2),benzyl azide (1 eq) in t-butanol (0.1M) was added sodium ascorbate (0.05eq), and copper (II) sulfate pentahydrate (0.01 eq). The resultingmixture was allowed to stir for 1 hour at room temperature. The mixturewas then diluted with water and the solid collect via suctionfiltration. MS: MH+ 531

Example 814

Step 1. Synthesis of 6-Nitro-indole-1-carboxylic acid t-butyl ester

To a stirring solution of 6-nitroindole (1 eq) in dichloromethane (0.3M)and DMF (3.1M), was added di-t-butyl dicarbonate (2 eq) followed by theaddition of 4-(dimethyl amino)pyridine (1 eq). Resulting solution wasallowed to stir overnight at room temperature. The dichloromethane wasthen removed on a rotovap and remaining solution diluted with water andextracted with ethyl acetate. Organics were washed with 10% citric acidsolution, saturated solution of sodium chloride, saturated solution ofsodium bicarbonate, saturated solution of sodium chloride and dried withsodium sulfate. Ethyl acetate was then removed in vacuo. Ethyl ether wasthen added and a brown solid was collected by suction filtration toyield 6-Nitro-indole-1-carboxylic acid t-butyl ester. MS: MH+ 263

Step 2. Synthesis of 6-Amino-2,3-dihydro-indole-1-carboxylic acidt-butyl ester

6-Nitro-indole-1-carboxylic acid t-butyl ester (1 eq) was dissolved inmethanol (0.1M), to this solution was added palladium on carbon (0.1 eq)in methanol under nitrogen. A hydrogen atmosphere was then inserted andresulting mixture allowed to stir for 3 hours at room temperature. Thereaction mixture was then filtered through celite and solvent removed invacuo to afford 6-Amino-2,3-dihydro-indole-1-carboxylic acid t-butylester as a white solid. MS: MH+ 235

Step 3. Synthesis of 6-Isothiocyanate-2,3-dihydro-indole-1-carboxylicacid t-butyl ester

Thiophosgene (1.1 eq) was added to a stirred suspension of6-Amino-2,3-dihydro-indole-1-carboxylic acid t-butyl ester (1 eq),sodium carbonate (10 eq), and dichloromethane:water 3:1 by volume at 0°C. The resulting mixture was allowed to stir for 2 hours at 0° C. Themixture was diluted with water and organics separated and washed withwater, saturated solution of sodium chloride and dried with sodiumsulfate, solvent removed in vacuo to afford6-Isothiocyanate-2,3-dihydro-indole-1-carboxylic acid t-butyl ester asorange oil.

Step 4. Synthesis of4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide

To a solution of 4-(4-Methylamino3-nitro-phenoxy)-pyridine-2-carboxylicacid methylamide (1 eq) in methanol (0.1M) was added palladium on carbon(0.1 eq) under nitrogen. The atmosphere was exchanged for hydrogen (1atm) and the resulting suspension allowed to stir for 2 hours at roomtemperature. The mixture was filtered through celite and added to6-Isothiocyanate-2,3-dihydro-indole-1-carboxylic acid t-butyl ester (1eq). The resulting solution was allowed to stir overnight. Iron (III)chloride (2 eq) in methanol was added and the solution turns deep red incolor. This solution was allowed to stir for 3 hours at roomtemperature. Methanol was then removed in vacuo; the resulting oil wasdiluted with water and extracted with dichloromethane. Organics werewashed with saturated sodium bicarbonate solution, water, and saturatedsodium chloride solution and dried with sodium sulfate. Solvent wasremoved in vacuo. To the resulting oil was added toluene and heated toreflux, solution was cooled to room temperature and a solid wascollected after 3 days by suction filtration to afford4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide. MS: MH+ 415

Example 815

Step 1. Synthesis of4-{1-Methyl-2-[1-(4-morpholin-4-yl-butyl)-2,3-dihydro-1H-indol-6-ylamino]-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylicacid methylamide

To mixture containing4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide (1 eq) (previously prepared using example 1), EDCI (2eq), HOAT (1.2 eq), DIEA (4 eq) was added THF. The mixture was allowedto stir overnight at room temperature under nitrogen. The mixture wasthen diluted with water, extracted with ethyl acetate. Organics werewashed with water, then saturated solution of sodium chloride and driedwith sodium sulfate, filtered and the solvent was removed in vacuo.Purification by chromatography yielded4-{1-Methyl-2-[1-(4-morpholin-4-yl-butyloyl)-2,3-dihydro-1H-indol-6-ylamino]-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylicacid methylamide. MS: MH+ 570

The compounds shown in the following table (Examples 816-819) wereprepared from following the procedure described for Example 815.

TABLE 12 Exam- ple Structure Name MH+ 816

4-{[2-(2,3-dihydro-1H- indol-6-ylamino)-1-methyl- 1H-benz-imidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 415.5 817

N-methyl-4-[(1-methyl-2- {[1-(3-pyridin-4-yl- propanoyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H- benzimidazol-5-yl)oxy] pyridine-2-carboxamide548.6 818

4-{[2-({1-[3-(1H-imidazol- 4-yl)-propanoyl]-2,3- dihydro-1H-indol-6-yl}amino)-1-methyl-1H-benz- imidazol-5-yl]oxy}-N- methyl-pyridine-2-carboxamide 537.6 819

N-methyl-4-[(1-methyl-2- {[1-(4-morpholin-4- ylbutanoyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H- benzimidazol-5-yl)oxy] pyridine-2-carboxamide570.7

Example 820

Step 1. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid

A stirring solution of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid tert-butylester in trifluoroacetic acid was treated with two drops of water atroom temperature for 3-4 hours or when the reaction was determined to becomplete by HPLC. The reaction was evaporated under reduced pressure toafford the product as a red-orange oil. Addition of ethyl ether,sonication, and filtration captures the product as a light pink solid.LCMS m/z 290.1 (MH+), tR=1.71 min.

Step 2. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide

To a suspension of the4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid (1 eq) indry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), and diisopropylethylamine (3eq) were added. The suspension was stirred for 10 minutes whereupon2,2-dimethyl-oxazolidine (1.1 eq) was added and the solution is allowedto stir overnight. The mixture was then diluted with ethyl acetate andwashed with water. The aqueous layer was washed with ethyl acetate, theorganic layers combined, dried over MgSO4, filtered, and concentrated.LCMS m/z 333.2 (MH+), tR=2.1 min.

Step 3. 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide

A solution of 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylicacid (2-hydroxy-ethyl)-amide (1 eq) and 10% palladium on carbon (0.1 eq)in methanol was stirred at room temperature and flushed with nitrogen.Hydrogen was flushed through the reaction for 1-2 hours or until thereaction was determined to be complete by HPLC. Nitrogen was flushedthrough the reaction for 15 minutes before the reaction was filteredthrough a celite pad. The celite pad was washed with excess methanolbefore it was all removed by evaporation under reduced pressure toafford the product as a light yellow solid. LCMS m/z 303.2 (MH+), tR=1.5min.

Step 4.4-[1-Methyl-2-(3-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (2-hydroxy-ethyl)-amide

A flask was charged with 3-(trifluoromethylthio)phenylisothiocyanate (1eq), 4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide (1 eq), and MeOH. The reaction was maintained atrt overnight. Ferric chloride, (1.5 eq) was added and the resulting redreaction mixture was stirred overnight. The reaction was partitionedwith EtOAc and water, and filtered through Celite. The layers wereseparated and the aqueous phase was neutralized with saturated Na2CO3solution. The resulting aqueous phase was extracted with EtOAc and themixture was filtered through Celite. The phases were separated and theaqueous phase was again extracted and filtered. The combined organiclayers were washed with brine, dried (MgSO4), filtered, and concentratedto give a brown solid. The crude residue was purified by reverse phaseHPLC. LCMS m/z 504.1 (MH+), tR=3.7 min.

Example 821

Step 1. Synthesis of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester

A round bottom flask was charged with 4-fluorophenylisothiocyanate (1eq), 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acidtert-butyl ester (1 eq), and MeOH. The reaction was maintained stirringat room temperature overnight. Ferric chloride, (1.5 eq) was added andthe resulting mixture was stirred overnight. The reaction waspartitioned with EtOAc and water, and filtered through Celite. Thelayers were separated and the aqueous phase was neutralized withsaturated Na2CO3 solution. The resulting aqueous phase was extractedwith EtOAc and the mixture was filtered through Celite. The phases wereseparated and the aqueous phase was again extracted and filtered. Thecombined organic layers were washed with brine, dried over MgSO4,filtered, and concentrated to give a brown solid. The crude residue waspurified by trituration in hot toluene to furnish the desired product.LCMS m/z 435.6 (MH+), tR=2.12 min.

Step 2. Synthesis of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid

A stirring solution of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester in trifluoroacetic acid was treated with two dropsof water at room temperature for 3-4 hours or when the reaction wasdetermined to be complete by HPLC. The reaction was evaporated underreduced pressure and then ether was added to the residue, which was thensonicated for 30 minutes. Filtration and washing with ether yields thedesired acid in quantitative yield. LCMS m/z 379.4 (MH+), tR=1.74 mm.

Step 3. Synthesis of{5-[2-(1H-Benzoimidazol-2-yl)-pyridin-4-yloxy]-1-methyl-1H-benzoimidazol-2-yl}-(4-fluoro-phenyl)-amine

To a suspension of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (1 eq) in dry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), anddiisopropylethylamine (3 eq) were added. The suspension was stirred for10 minutes whereupon phenylenediamine (1.1 eq) was added and thesolution is allowed to stir overnight. The mixture was then diluted withethyl acetate and washed with water. The aqueous layer was washed withethyl acetate, the organic layers combined, dried over MgSO4, filtered,and concentrated. Acetic acid was added to the residue followed bysodium acetate (1.1 eq). The mixture was heated for 3 hours at 70° C.,whereupon the solution is concentrated and the residue purified byreverse phase HPLC to afford the desired product. LCMS m/z 451.5 (MH+),tR=1.92 min.

Synthesis of Side Chains Ether Substituted Phenylenediamines:

4-(3-Bromopropoxy)-2-nitrophenylamine

A flask is charged with 4-amino-3-nitrophenol 1 (1 eq), K₂CO₃ (2 eq),and 2-butanone. 1,3-dibromopropane 2 (1.5 eq) is added and the mixtureis heated at 80° C. for 18 hours. After cooling, the mixture is filteredconcentrated and water is added. The solution is then extracted withCH₂Cl₂ (×3), the organic layer concentrated, and the solid recoveredwashed with pentane to yield the desired product 3. LCMS m/z 275.1(MH+), R_(t) 2.74 minutes.

2-Nitro-4-(3-pyrrolidinylpropoxy)phenylamine

4-(3-bromopropoxy)-2-nitrophenylamine 1 (1 eq) was heated to 70° C. withpyrrolidine 2 (5 eq) in MeCN with Cs₂CO₃ (2 eq) and Bu₄NI (0.1 eq) for48 hours. The reaction mixture was cooled, filtered, and concentrated.The residue is dissolved in CH₂Cl₂, and washed with water. The organiclayer is concentrated yielding the desired product 3. LCMS m/z 266.2(MH+), R_(t) 1.51 minutes.

4-(3-Pyrrolidinylpropoxy)benzene-1,2-diamine

To a solution 2-Nitro-4-(3-pyrrolidinylpropoxy)phenylamine 1 in EtOH,Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3)with nitrogen, and then stirred under a hydrogen atmosphere for 18 h.The product is filtered through a Celite plug, and the plug washed with25 mL of EtOH, to yield 2. LCMS 236.2 R_(t) 0.94 min.

3-Fluoro-4-amino substituted phenylenediamines

1. Synthesis of 2-Fluoro-3-(4-methyl-piperazin-1-yl)-6-nitro-phenylamine

A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq)and 5,6-difluoro-2-nitroaniline (1.0 eq) were heated at 90° C. for 1hour. The reaction was allowed to cool to room temperature and thenpoured into water and let stand for 1 hour. The resulting solid wascollected and dried and utilized without further purification. MH+=255.3

2. Synthesis of 3-Fluoro-4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine

To a solution Synthesis of2-fluoro-3-(4-methyl-piperazin-1-yl)-6-nitrophenylamine in EtOH, Pd/C(0.1 eq) is added. The reaction vessel is repeatedly purged (×3) withnitrogen, and then stirred under a hydrogen atmosphere for 18 h. Theproduct is filtered through a Celite plug, the plug washed with 25 mL ofEtOH, to yield the desired diamine. LCMS 225.3 Rt 0.45 min.

4-Amino substituted phenylenediamines (a)

Synthesis of 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine

A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq)and 5-fluoro-2-nitrophenylamine (1.0 eq) were heated at 90° C. for 1hours. The reaction was allowed to cool to room temperature and thenpoured into water and let stand for 12 hours. The resulting solid wascollected and dried and utilized without further purification.MH+=237.3.

Synthesis of 4-(4-Methyl-piperazin-1-yl)-benzene-1,2-diamine

To a solution 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine in EtOH,Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3)with nitrogen, then stirred under a hydrogen atmosphere for 18 h. Theproduct is filtered through a Celite plug, the plug washed with 25 mL ofEtOH, to yield the desired diamine. LCMS 207.3 Rt 0.25 min.

4-Amino substituted phenylenediamines (b)

Synthesis of 5-(4-Cyclopentyl-piperazin-1-yl)-2-nitro-phenylamine

1. A solution of N-cyclopentylpiperazine (1.0 eq), NMP, triethylamine(3.0 eq) and 5-fluoro-2-nitrophenylamine (1.0 eq) were heated at 90° C.for 1 hours. The reaction was allowed to cool to room temperature andthen poured into water and let stand for 12 hours. The resulting solidwas collected and dried and utilized without further purification.MH+=291.4.

2. Synthesis of 4-(4-Cyclopentyl-piperazin-1-yl)-benzene-1,2-diamine:

To a solution 5-(4-Cyclopentyl-piperazin-1-yl)-2-nitro-phenylamine inEtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged(×3) with nitrogen, then stirred under a hydrogen atmosphere for 18 h.The product is filtered through a Celite plug, the plug washed with 25mL of EtOH, to yield the desired diamine. MH+=261.3.

Example 822

Step 1. Synthesis of 4-Chloro-pyridine-2-carboxylic acid dimethylamide

A solution of 4-chloro-pyridine-2-carbonyl chloride (1 eq) indichloromethane was cooled to 0° C., whereupon triethylamine (2 eq) wasadded followed by dimethylamine (2 eq, 2M solution in THF). The solutionwas allowed to warm to room temperature and let stir overnight. It wasthen washed with 1M NaOH. The separated organic layer is dried overMgSO4, filtered, and concentrated to yield the desired product. HPLC,1.82 min; MS: MH+=185.6

Step 2. Synthesis of 4-(4-Amino-3-nitro-phenoxy)-pyridine-2-carboxylicacid dimethylamide

A mixture containing 4-amino-3-nitrophenol (1 eq) and potassiumbis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2hours at room temperature. To this mixture was added4-Chloro-pyridine-2-carboxylic acid dimethylamide (1 eq) and potassiumcarbonate (1.2 eq) and then it was stirred at 90° C. for 3 days. Thereaction mixture was then concentrated before partitioning between ethylacetate and water. The organic layer was separated, washed with brine,dried, filtered and concentrated in vacuum to give brown solid.Purification by flash chromatography with ethyl acetate and hexane (1:1)gave the desired product as a yellow syrup. HPLC, 1.69 min; MS:MH+=303.1.

Step 3. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic aciddimethylamide

A solution of 4-(4-Amino-3-nitro-phenoxy)-pyridine-2-carboxylic aciddimethylamide (1 eq) in methylene chloride was treated withtrifluoroacetic anhydride (1 eq) and stirred for 10 minutes at 0° C. Themixture was quenched with satd. NaHCO3 solution. The organic layer wasseparated and washed with water, brine, dried, filtered and evaporated.MS: MH+=399.0

To the solution of the trifluoroacetamide (1 eq) in a mixture oftoluene, acetonitrile and sodium hydroxide solution (50%) was addedbenzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq).The biphasic mixture was stirred overnight at room temperature. Themixture was taken up in ethyl acetate, washed with water, brine, driedand evaporated. The crude was purified by flash chromatography elutingwith 5% methanol in dichloromethane to afford the desired product. HPLC,2.14 min; MS: MH+=317.3

Step 4. Synthesis of4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic aciddimethylamide

The solution of 4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylicacid dimethylamide in methanol was treated with 10% palladium on carbonand stirred under hydrogen atmosphere for 3 hours at room temperature.The mixture was purged with nitrogen and then was filtered throughcelite and the filtrate was concentrated to provide the diamine. HPLC,1.17 min; MS: MH+=287.1

Step 5. Synthesis of4-[2-(2,6-Difluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid dimethylamide

A solution of the4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic aciddimethylamide (1 eq) in methanol was treated with2,6-difluorophenylisothiocyanate (1 eq) and stirred overnight. To thereaction mixture, methyl iodide (1 eq) was added and stirred overnightat 60° C. The reaction was cooled down to room temperature, evaporated,and the residue purified by reverse phase HPLC. HPLC, 1.66 min; MS:MH+=424.1

Each of the compounds 823-984, listed in the below table weresynthesized as indicated in the right hand column by the methoddescribed herein.

TABLE 13 Ex- Synthe- am- sized as ple Structure Name MH+ in Ex.: 823

4-({2-[(2,6-difluorophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.1 822 824

N,N-dimethyl-4-[(1-methyl-2- {[2-(trifluoromethyl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 456.4 822 825

4-({2-[(4-ethylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N,N-dimethylpyridine-2- carboxamide 416.5 822 826

4-({2-[(3,5-difluorophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.4 822 827

4-({2-[(2,4-dimethylphenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 416.5 822 828

N,N-dimethyl-4-{[1-methyl-2- ({2-[(trifluoromethyl)oxy]-phenyl}amino)-1H-benz- imidazol-5-yl]oxy}pyridine-2- carboxamide 472.4822 829

4-({2-[(2,5-difluorophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.4 822 830

4-({2-[(3-ethylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N,N-dimethylpyridine-2- carboxamide 416.5 822 831

4-[(2-{[2-chloro-5-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N,N-dimethylpyridine-2- carboxamide490.9 822 832

4-[(2-{[2-fluoro-5-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N,N-dimethylpyridine-2- carboxamide474.4 822 833

N,N-dimethyl-4-[(1-methyl-2- {[2-(methylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 434.5 822 834

4-({2-[(2,4-difluorophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.4 822 835

4-({2-[(2,3-dimethylphenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 416.5 822 836

4-[(2-{[4-chloro-2-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N,N-dimethylpyridine-2- carboxamide490.9 822 837

4-({2-[(3-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 436.9 822 838

4-[(2-{[5-chloro-2-(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N- dimethylpyridine-2-carboxamide 452.9 822 839

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N- dimethylpyridine-2-carboxamide 448.5 822 840

N,N-dimethyl-4-[(1-methyl-2- {[5-methyl-2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 432.5822 841

N,N-dimethyl-4-[(1-methyl-2- {[4-(methyloxy)-1,1′-biphenyl-3-yl]amino}-1H-benzimidazol- 5-yl)oxy]pyridine-2-carbox- amide 494.6 822842

4-[(2-{[3,4-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N- dimethylpyridine-2-carboxamide 448.5 822 843

N,N-dimethyl-4-[(1-methyl-2- [2-(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 418.5 822 844

4-[(2-{[5-chloro-2,4-bis(methyl- oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N,N-dimethylpyridine-2- carboxamide 482.9 822845

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(1- methylpyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide 531.6 372 846

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (dimethylamino)ethyl]pyridine 2-carboxamide491.6 372 847

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3- (methyloxy)propyl]pyridine-2- carboxamide492.5 372 848

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (methyloxy)ethyl]pyridine-2- carboxamide478.5 372 849

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4- methylpiperazin-1-yl)propyl]-pyridine-2-carboxamide 560.7 372 850

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3- morpholin-4-ylpropyl)pyridine-2-carboxamide 547.6 372 851

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (1,2,2,6,6-pentamethylpiperidin-4-yl)pyridine-2-carboxamide 573.7 372 852

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2- morpholin-4-ylethyl)pyridine-2- carboxamide533.6 372 853

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methyl-N-propylpyridine-2- carboxamide 476.5372 854

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methyl-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide 492.5 372 855

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (dimethylamino)ethyl]-N-methylpyridine-2-carboxamide 505.6 372 856

5-{[2-(1H-benzimidazol-2-yl)- pyridin-4-yl]oxy}-N-[3,5-bis-(methyloxy)phenyl]-1-methyl- 1H-benzimidazol-2-amine 493.5 821 857

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-imidazol-4- yl)ethyl]pyridine-2-carboxamide 472.5 372858

N-[2-(dimethylamino)ethyl]-4- ({2-[(2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 449.5 372 859

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]pyridine-2- carboxamide489.6 372 860

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-indol-3-yl)- ethyl]pyridine-2-carboxamide 521.6 372 861

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide 450.5 372 862

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)- ethyl]pyridine-2-carboxamide 436.5 372 863

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 483.5 372 864

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methyl- piperazin-1-yl)propyl]pyridine- 2-carboxamide518.6 372 865

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-morpholin-4-yl- propyl)pyridine-2-carboxamide 505.6 372 866

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(2-pyridin- 4-ylethyl)pyridine-2-carbox- amide 497.5372 867

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-({2-[(2-fluorophenyl)-amino]-1-methyl-1H-benz- imidazol-5-yl}oxy)pyridine-2- carboxamide 489.6372 868

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,2,2,6,6-penta- methylpiperidin-4-yl)pyridine-2- carboxamide531.6 372 869

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-propyl- pyridine-2-carboxamide 434.5 372 870

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-yl- ethyl)pyridine-2-carboxamide 491.5 372 871

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-[2-(methyl- oxy)ethyl]pyridine-2-carbox- amide 450.5372 872

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(1-methyl- piperidin-4-yl)pyridine-2- carboxamide489.6 372 873

N-[2-(dimethylamino)ethyl]-4- ({2-[(2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 463.5372 874

N-[2-(1H-imidazol-4-yl)ethyl]- 4-[(1-methyl-2-{[2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 484.5372 875

N-[2-(dimethylamino)ethyl]-4- [(1-methyl-2-{[2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 461.5372 876

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[2-(1- methylpyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide 501.6 372 877

N-[2-(1H-indol-3-yl)ethyl]-4- [(1-methyl-2-{[2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 533.6372 878

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[3- (methyloxy)propyl]pyridine-2- carboxamide 462.5372 879

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[2- (methyloxy)ethyl]pyridine-2- carboxamide 448.5372 880

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-(2- pyridin-4-ylethyl)pyridine-2- carboxamide 495.6372 881

4-[(1-methyl-2-{[2-(methyl- oxy)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[3-(4- methylpiperazin-1-yl)propyl]-pyridine-2-carboxamide 530.6 372 882

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-(3- morpholin-4-ylpropyl)pyridine- 2-carboxamide517.6 372 883

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- pyridin-4-ylethyl)pyridine-2- carboxamide509.6 372 884

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-[(1-methyl-2-{[2-(methyloxy)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 501.6 372 885

4-[(1-methyl-2-{[2-(methyl- oxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- (1,2,2,6,6-pentamethylpiperidin-4-yl)pyridine-2-carboxamide 543.7 372 886

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-[2- (methyloxy)ethyl]pyridine-2- carboxamide462.5 372 887

4-[(1-methyl-2-{[2-(methyl- oxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- morpholin-4-ylethyl)pyridine-2- carboxamide503.6 372 888

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- propylpyridine-2-carboxamide 446.5 372 889

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(1- methylpiperidin-4-yl)pyridine-2-carboxamide 501.6 372 890

N-[2-(dimethylamino)ethyl]-N- methyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 475.6 372 891

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-1-methyl-N-[2-(methyloxy)phenyl]-1H- benzimidazol-2-amine 463.5 372 892

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-N-(2-fluorophenyl)-1-methyl-1H- benzimidazol-2-amine 451.5 372 893

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-imidazol-4- yl)ethyl]pyridine-2-carboxamide 472.5 372894

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]pyridine-2- carboxamide489.6 372 895

N-[2-(dimethylamino)ethyl]-4- ({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 449.6 372 896

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-indol-3-yl)- ethyl]pyridine-2-carboxamide 521.6 372 897

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide 450.5 372 898

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)- ethyl]pyridine-2-carboxamide 436.5 372 899

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 483.6 372 900

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methyl- piperazin-1-yl)propyl]pyridine- 2-carboxamide518.6 372 901

5-{[2-({(2R,5R)-2-[(dimethyl- amino)methyl]-5-methyl-morpholin-4-yl}carbonyl)- pyridin-4-yl]oxy}-N-(4-fluoro-phenyl)-1-methyl-1H-benz- imidazol-2-amine 519.6 372 902

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-morpholin-4-yl- propyl)pyridine-2-carboxamide 505.6 372 903

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(2-pyridin- 4-ylethyl)pyridine-2-carbox- amide 497.6372 904

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 489.6 372 905

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,2,2,6,6-penta- methylpiperidin-4-yl)pyridine-2- carboxamide531.7 372 906

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-[2-(methyl- oxy)ethyl]pyridine-2-carbox- amide 450.6372 907

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-yl- ethyl)pyridine-2-carboxamide 491.6 372 908

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine-2- carboxamide 434.6 372 909

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(1-methyl- piperidin-4-yl)pyridine-2- carboxamide489.6 372 910

N-[2-(dimethylamino)ethyl]-4- ({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 463.6372 911

5-{[2-({(2R,5S)-2-[(dimethyl- amino)methyl]-5-methyl-morpholin-4-yl}carbonyl)- pyridin-4-yl]oxy}-N-(4-fluoro-phenyl)-1-methyl-1H-benz- imidazol-2-amine 519.6 372 912

5-{[2-(1H-benzimidazol-2-yl)- pyridin-4-yl]oxy}-N-(4-fluoro-phenyl)-1-methyl-1H-benz- imidazol-2-amine 451.5 821 913

4-({2-[(4-bromo-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 471.3  120a 914

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-phenylethyl)- pyridine-2-carboxamide 499.0 372 915

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-{2-[2-(methyloxy)- phenyl]ethyl}pyridine-2-carbox- amide 529.0372 916

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)- ethyl]pyridine-2-carboxamide 466.0 372 917

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 500.0 372 918

N-(4-chlorophenyl)-5-{[2- ({(2R,5R)-2-[(dimethylamino)-methyl]-5-methylmorpholin-4- yl}carbonyl)pyridin-4-yl]oxy}-1-methyl-1H-benzimidazol-2- amine 536.0 372 919

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(2-pyridin- 4-ylethyl)pyridine-2- carboxamide 514.0372 920

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,2,2,6,6-penta- methylpiperidin-4-yl)pyridine-2- carboxamide548.1 372 921

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-propyl- pyridine-2-carboxamide 450.9 372 922

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(1-methyl- piperidin-4-yl)pyridine-2- carboxamide506.0 372 923

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)- ethyl]-N-methylpyridine-2- carboxamide480.0 372 924

N-(4-chlorophenyl)-5-{[2- ({(2R,5S)-2-[(dimethylamino)-methyl]-5-methylmorpholin-4- yl}carbonyl)pyridin-4-yl]oxy}-1-methyl-1H-benzimidazol-2- amine 536.0 372 925

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-[2-(methyl- oxy)ethyl]pyridine-2-carbox- amide 466.9372 926

N-(4-fluorophenyl)-5-{[2-(3H- imidazo[4,5-b]pyridin-2-yl)-pyridin-4-yl]oxy}-1-methyl-1H- benzimidazol-2-amine 452.5 821 927

N-(4-fluorophenyl)-1-methyl-5- {[2-(1H-naphtho[2,3-d]-imidazol-2-yl)pyridin-4-yl]oxy}- 1H-benzimidazol-2-amine 501.5 821 928

N-(4-fluorophenyl)-1-methyl-5- {[2-(5-methyl-1H-benzimidazol-2-yl)pyridin-4-yl]oxy}-1H- benzimidazol-2-amine 465.5 821 929

N-(4-fluorophenyl)-1-methyl-5- ({2-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]pyridin-4- yl}oxy)-1H-benzimidazol-2- amine 549.6821 930

N-(4-fluorophenyl)-1-methyl-5- {[2-(1-methyl-1H-benzimidazol-2-yl)pyridin-4-yl]oxy}-1H- benzimidazol-2-amine 465.5 821 931

5-({2-[5-(1,1-dimethylethyl)- 1H-benzimidazol-2-yl]pyridin-4-yl}oxy)-N-(4-fluorophenyl)-1- methyl-1H-benzimidazol-2- amine 507.6 821932

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-[(1-methyl-2-{[3-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 539.3 372 933

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- morpholin-4-ylethyl)pyridine-2- carboxamide541.3 372 934

N-[3-(4-methylpiperazin-1-yl)- propyl]-4-[(1-methyl-2-{[3-(tri-fluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 568.4 372 935

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-1,3- thiazol-2-ylpyridine-2-carbox- amide 511.2372 936

N-[2-(1-methylpyrrolidin-2-yl)- ethyl]-4-[(1-methyl-2-{[3-(tri-fluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 539.3 372 937

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-[2-(2- oxoimidazolidin-1-yl)ethyl]-pyridine-2-carboxamide 540.3 372 938

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- pyrrolidin-1-ylethyl)pyridine-2-carboxamide 525.3 372 939

N-[3-(1H-imidazol-1-yl)propyl]- 4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine- 2-carboxamide536.3 372 940

N-[2-(methyloxy)ethyl]-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 486.3372 941

N-(2-hydroxyethyl)-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 472.2372 942

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- piperidin-1-ylethyl)pyridine-2- carboxamide539.3 372 943

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(3- piperidin-1-ylpropyl)pyridine-2-carboxamide 553.3 372 944

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(3- pyrrolidin-1-ylpropyl)pyridine-2-carboxamide 539.3 372 945

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- pyridin-4-ylethyl)pyridine-2- carboxamide533.3 372 946

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- piperazin-1-ylethyl)pyridine-2- carboxamide540.2 372 947

N-[3-(methyloxy)propyl]-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 500.2372 948

N-[2-(acetylamino)ethyl]-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 513.3372 949

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- pyrrolidin-3-ylpyridine-2- carboxamide 497.2372 950

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-[3-(2- oxopyrrolidin-1-yl)propyl]-pyridine-2-carboxamide 553.3 372 951

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- propylpyridine-2-carboxamide 470.3 372 952

N-ethyl-4-[(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 456.2 372 953

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]- 1H-benzimidazol-2-amine 501.2 821 954

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-1-methyl-N-[3-(1-methylethyl)phenyl]- 1H-benzimidazol-2-amine abran 821 955

1-methyl-5-{[2-(5-methyl-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-N-[3-(trifluoromethyl)- phenyl]-1H-benzimidazol-2- amine 515.2821 956

1-methyl-5-{[2-(1H- naphtho[2,3-d]imidazol-2-yl)-pyridin-4-yl]oxy}-N-[3-(tri- fluoromethyl)phenyl]-1H-benzimidazol-2-amine 551.3 821 957

1-methyl-5-{[2-(1-methyl-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-N-[3-(trifluoromethyl)- phenyl]-1H-benzimidazol-2- amine 515.2821 958

(2-{4-[(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridin-2-yl}-1H-benzimidazol-5-yl)(phenyl)methanone 605.2 821 959

5-{[2-(5-bromo-1H- benzimidazol-2-yl)pyridin-4- yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 579.1 821 960

5-{[2-(5-chloro-6-fluoro-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-1-methyl-N-[3- (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine553.2 821 961

5-{[2-(5-chloro-1H- benzimidazol-2-yl)pyridin-4- yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 535.2 821 962

5-{[2-(5-fluoro-1H- benzimidazol-2-yl)pyridin-4- yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 519.4 821 963

1-methyl-5-({2-[5- (trifluoromethyl)-1H- benzimidazol-2-yl]pyridin-4-yl}oxy)-N-[3- (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 569.2821 964

methyl 2-{4-[(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5- yl)oxy]pyridin-2-yl}-1H- benzimidazole-5-carboxylate559.2 821 965

5-{[2-(5,6-dichloro-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-1-methyl-N-[3- (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine569.1 821 966

5-({2-[5-(1,1-dimethylethyl)- 1H-benzimidazol-2-yl]pyridin-4-yl}oxy)-1-methyl-N-[3- (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine557.3 821 967

1-methyl-5-{[2-(3-phenyl-1,2,4- oxadiazol-5-yl)pyridin-4- yl]oxy}-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 529.2 821 968

5-({2-[7-fluoro-6-(4-methyl- piperazin-1-yl)-1H-benzimidazol-2-yl]pyridin-4- yl}oxy)-1-methyl-N-[3-(1-methylethyl)phenyl]-1H- benzimidazol-2-amine 591.3 821 969

1-methyl-N-[3-(1-methyl- ethyl)phenyl]-5-[(2-{5-[(3-pyrrolidin-1-ylpropyl)oxy]-1H- benzimidazol-2-yl}pyridin-4-yl)oxy]-1H-benzimidazol-2- amine 602.7 821 970

N-(2-hydroxyethyl)-4-{[1- methyl-2-({3-[(trifluoromethyl)-thio]phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide504.1 820 971

N-(2-hydroxyethyl)-4-{[1- methyl-2-({4-[(trifluoromethyl)-thio]phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide504.1 820 972

4-({2-[(3-fluoro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 436.2820 973

4-({2-[(4-bromo-3-chloro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 516  820 974

4-({2-[(4-chloro-3-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 452.2820 975

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)- pyridine-2-carboxamide 422.2 820 976

4-({2-[(3-chloro-4-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 456.2820 977

N-(2-hydroxyethyl)-4-[(1- methyl-2-{[4-methyl-3-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 486.2 820 978

4-({2-[(3-chloro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 452.2820 979

4-({2-[(4-bromo-3-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2-carbox- amide 502.1820 980

5-({2-[4-fluoro-5-(4-methyl- piperazin-1-yl)-1H-benz-imidazol-2-yl]pyridin-4-yl}oxy)- 1-methyl-N-[3-(trifluoromethyl)-phenyl]-1H-benzimidazol-2- amine 428.2 821 981

5-{[2-(1H-benzimidazol-2-yl)- pyridin-4-yl]oxy}-N-(4-chloro-3-pyridin-4-ylphenyl)-1-methyl- 1H-benzimidazol-2-amine 545.0 821 982

1-methyl-5-{[2-(5-{[2-(methyl- oxy)ethyl]oxy}-1H-benz-imidazol-2-yl)pyridin-4-yl]oxy}- N-{3-[(trifluoromethyl)thio]-phenyl}-1H-benzimidazol-2- amine 607.2 821 983

5-({2-[5-(4-cyclopentyl- piperazin-1-yl)-1H-benz-imidazol-2-yl]pyridin-4-yl}oxy)- 1-methyl-N-{3-[(trifluoro-methyl)thio]phenyl}-1H- benzimidazol-2-amine 685.3 821 984

1-methyl-N-(3-pyridin-4-yl- phenyl)-5-({2-[5-(trifluoro-methyl)-1H-benzimidazol-2- yl]pyridin-4-yl}oxy)-1H- benzimidazol-2-amine578.3 821

Example 985 Synthesis of Oxime Series:4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehydeoxime Step 1. Synthesis of[4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-yl]-methanol

A flame dried 500 mL three-necked round bottom flask purged with N₂ wascharged with LAH (2.32 g, 58.0 mmol) and dry THF (60 mL). The resultingsuspension was cooled to 0° C. and a suspension of t-butyl ester 1 (10.0g, 29.0 mmol) in dry THF (60 mL) was slowly added while keeping theinternal reaction temperature under 5° C. The reaction was stirred at 0°C. for 30 min then at rt for 30 min. After the reaction was judgedcomplete, the mixture was treated with successive dropwise addition ofwater (2.3 mL), 10% NaOH (2.3 mL), and water (7.2 mL). The resultingsuspension was filtered through Celite, washed with ethyl acetate andmethanol, and the collected organics concentrated. The crude product wasabsorbed onto silica gel and purified by flash chromatography (97:3CH₂Cl₂/MeOH) to give 2 as an orange solid: ¹H NMR (300 MHz, CDCl₃) δ8.40 (d, J=5.5 Hz, 1H), 8.05 (br s, 1H), 7.96 (d, J=2.75 Hz, 1H), 7.29(d, J=2.75 Hz, 1H), 6.92 (d, J=9.35 Hz, 1H), 6.75 (m, 2H), 4.68 (s, 2H),3.07 (d, J=5.23 Hz, 3H).

Step 2. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde

A 250 mL reaction tube was charged with benzyl alcohol 1 (1.0 g, 3.6mmol), MnO₂ (4.7 g, 54 mmol) and EtOAc (20 mL). The reaction tube wassealed was heated to 120° C. with stirring for 2 h. The reaction wasallowed to cool to rt, then filtered through Celite and washedsuccessively with EtOAc, MeOH, and EtOH. The combine organics wereconcentrated to give 936 mg (3.4 mmol, 94%) of 2 as an orange solid: ¹HNMR (300 MHz, CDCl₃) δ 10.01 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.09 (brs, 1H), 7.96 (d, J=2.75 Hz, 1H), 7.37 (d, J=2.48 Hz, 1H), 7.29 (d,J=2.75 Hz, 1H), 7.08 (dd, J=2.47, 5.5 Hz, 1H), 6.94 (d, J=9.35 Hz, 1H),3.08 (d, J=5.23 Hz, 3H).

Step 3. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde oxime

A 50 mL round bottom flask was charged with 1 (680 mg, 2.5 mmol),hydroxylamine HCl (191 mg, 2.75 mmol), pyridine (0.25 mL, 3.0 mmol) andethanol (10 mL). The resulting reaction mixture was stirred at rtovernight. The crude product was concentrated, absorbed onto silica gel,and purified by flash chromatography (97:3 CH₂Cl₂/MeOH to give 2 as anorange solid. LCMS m/z 289.2 (MH⁺), t_(R)=2.06 min.

Step 4. Synthesis of4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carbaldehyde oxime

A reaction tube was charged with suspension of 1 (330 mg, 1.15 mmol) andLindlar catalyst (245 mg, 10 mol %) in methanol (5 mL), sealed, andplaced on a Parr shaker. The reaction was pressurized with H₂ (60 psi)and maintained for 1 h. The reaction was filtered through Celite and theremaining solids were washed with MeOH. The combined organics wereconcentrated to give 2 as a brown semi-solid which was taken on withoutfurther purification.

Step 5. Synthesis of4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehydeoxime

A 5 mL round bottom flask was charged with 4-bromophenylisothiocyanate(54 mg, 0.25 mmol), diamine 1 (65 mg, 0.25 mmol), and MeOH (1 mL). Theresulting reaction was maintained at rt overnight. Methyl iodide (20 μL,0.33 mmol) was added to the reaction and stirred overnight. The reactionwas concentrated and the resulting residue was purified by reverse-phaseHPLC. LCMS m/z 438.1 (MH⁺), t_(R)=1.87 min.

Example 986 Synthesis of O-methyl-oxime Series:4-[1-Methyl-2-(4-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehydeO-methyl-oxime Step 1. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde O-methyl-oxime

A 25 mL round bottom flask was charged with a suspension of 1 (600 mg,2.2 mmol), methoxylamine HCl (202 mg, 2.42 mmol), and pyridine (0.22 mL,2.6 mmol) in ethanol (9 mL). The resulting reaction mixture was stirredat rt overnight. The crude product was concentrated, absorbed ontosilica gel, and purified by flash chromatography (97:3 CH₂Cl₂/MeOH) togive 2 as an orange solid. LCMS m/z 303.2 (MH⁺), t_(R)=2.40 mm.

Step 2. Synthesis of4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carbaldehyde O-methyl-oxime

A reaction tube was charged with a suspension of 1 (270 mg, 0.9 mmol)and Lindlar catalyst (192 mg, 10 mol %) in methanol (5 mL), and was thenplaced on a Parr shaker. The was reaction pressurized with H₂ (60 psi)and maintained for 1 h. The reaction was filtered through Celite and theremained solids were washed with methanol. The combined organics wereconcentrated to give 2 as a brown semi-solid which was carried forwardwithout further purification LCMS m/z 273.3 (MH⁺), t_(R)=1.56 min.

Step 3. Synthesis of4-[1-Methyl-2-(4-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehydeO-methyl-oxime

A 5 mL round bottom flask was charged with4-trifluoromethylthio-phenylisothiocyanate (24 mg, 0.1 mmol), diamine 1(27 mg, 0.1 mmol), and MeOH (0.5 mL). The reaction was maintained at rtovernight, after which methyl iodide (8 μL, 0.13 mmol) was added. After16 h, the reaction was concentrated and the resulting residue waspurified by reverse-phase HPLC. LCMS m/z 474.3 (MH⁺), t_(R)=2.42 min.

Example 987

Synthesized as described in Example 986 step 3 using 4-bromophenylisothiocyanate. LCMS m/z 402.4 (MH⁺), t_(R)=2.15 min.

Example 988

Synthesized as described in Example 986 step 3 using4-ethylphenylisothiocyanate. LCMS m/z 402.4 (MH⁺), t_(R)=2.15 min.

Example 989

Synthesized as described in Example 986 step 3 using4-bromo-2-trifluoro-methoxyphenylisothiocyanate. LCMS m/z 536.2 (MH⁺),t_(R)=2.38 min.

Example 990

Synthesized as described in Example 986 step 3 using2,4-dimethylphenylisothiocyanate. LCMS m/z 402, (MH⁺), t_(R)=2.07 min.

Example 991 Synthesis of Benzyl Alcohol Series:{4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-methanolStep 1. Synthesis of[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-methanol

A suspension of nitroaniline 1 (550 mg, 2.0 mmol) in methanol wassparged with N₂ for 20 min after which 10% Pd/C (106 mg, 0.1 mmol) wasadded. The reaction was charged with H₂ and maintained under a H₂atmosphere overnight at rt. The reaction was sparged with N₂ andfiltered through Celite. The collected solids were washed with EtOAc(3×50 mL), and the combined organic layers were dried (MgSO₄) andconcentrated to afford 2, which was taken on without furtherpurification.

Step 2. Synthesis of{4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-methanol

A 5 mL round bottom flask was charged with 4-chlorophenylisothiocyanate(34 g, 0.2 mmol), diamine 1 (49 mg, 0.2 mmol), and MeOH (1 mL) and theresulting reaction was maintained at rt overnight. Ferric chloride (16mg, 0.1 mmol) was added and the red reaction mixture was stirredovernight. The reaction was partitioned with EtOAc and water, the layerswere separated and the aqueous phase was neutralized (pH=7) withsaturated aqueous Na₂CO₃ solution. The aqueous phase was extracted withEtOAc. The combined organic layers were washed with brine, dried, andconcentrated to give a brown solid. The reaction was concentrated andthe resulting residue purified on reverse-phase HPLC. LCMS m/z 381.3(MH⁺), t_(R)=2.27 min.

Example 992

Synthesized as described in Example 1058 step 2 using4-fluorophenylisothiocyanate. LCMS m/z 365.4 (MH⁺), t_(R)=2.04 min.

Example 993

Synthesized as described in Example 991 step 2 using4-bromo-3-methylphenylisothiocyanate. LCMS m/z 439.3 (MH⁺), t_(R)=2.79min.

Example 994

Synthesized as described in Example 991 step 2 using4-bromo-2-trifluoromethoxyphenylisothiocyanate. LCMS m/z 511.3 (MH⁺),t_(R)=3.08 min.

Example 995

Synthesized as described in Example 991 step 2 using4-methylthiophenylisothiocyanate. LCMS m/z 393.4 (MH⁺), t_(R)=2.46 min.

Example 995

Synthesized as described in Example 991 step 2 using3-ethylphenylisothiocyanate. LCMS m/z 375.4 (MH⁺), t_(R)=2.57 min.

Example 996

Synthesized as described in Example 991 step 2 using4-trifluoromethylthio-phenylisothiocyanate. LCMS m/z 447.3 (MH⁺),t_(R)=3.21 min.

Example 997

Synthesized as described in Example 991 step 2 using3-iodophenylisothiocyanate. LCMS m/z 473.2 (MH⁺), t_(R)=2.57 min.

Example 998

Synthesized as described in Example 991 step 2 using3-trifluoromethylthiophenylisothiocyanate. LCMS m/z 447.3 (MH⁺),t_(R)=3.08 min.

Example 9994-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid phenylamide Procedure for Synthesis of Anilide Series (4-Br and3-iPr West-Ends) Synthesis of4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid phenylamide

A suspension of 1 (44 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol), and DIEA(43 uL, 0.25 mmol) in NMP (0.5 mL) was shaken for 30 min at rt. Anilinewas added and the reaction was shaken overnight. The crude productpurified on reverse-phase HPLC. LCMS m/z 515.2 (MH⁺), t_(R)=2.75 min.

Example 1000

Synthesized as described in Example 999 using N,O-dimethylhydroxylamineHCl. LCMS m/z 483.3 (MH⁺), t_(R)=2.07 min.

Example 1001

Synthesized as described in Example 999 using 4-bromoaniline. LCMS m/z594.0 (MH⁺), t_(R)=5.39 min.

Example 1002

Synthesized as described in Example 999 using 3,4-dimethylaniline. LCMSm/z 543.2 (MH⁺), t_(R)=5.39 min.

Example 1003

Synthesized as described in Example 999 using 3-trifluoromethylaniline.LCMS m/z 583.1 (MH⁺), t_(R)=3.12 min.

Example 1004

Synthesized as described in Example 999 using 3-chloroaniline. LCMS m/z550.1 (MH⁺), t_(R)=5.28 min.

Example 1005

Synthesized as described in Example 999 using 3-ethylaniline. LCMS m/z543.2 (MH⁺), t_(R)=3.16 min.

Example 1006

Synthesized as described in Example 1067 using 4-methylaniline. LCMS m/z529.2 (MH⁺), t_(R)=5.15 min.

Example 1007

Synthesized as described in Example 999 using 3-isopropylaniline. LCMSm/z 520.3 (MH⁺), t_(R)=5.98 min.

Example 1008

Synthesized as described in Example 999 using 3-tert-butylaniline. LCMSm/z 534.3 (MH⁺), t_(R)=3.32 min.

Example 1009

Synthesized as described in Example 999 using 3-trifluoromethoxyaniline.LCMS m/z 562.2 (MH⁺), t_(R)=3.15 min.

Example 1010

Synthesized as described in Example 999 using 3-biphenylamine. LCMS m/z554.3 (MH⁺), t_(R)=3.28 min.

Example 1011

Synthesized as described in Example 999 using 4-bromoaniline. LCMS-m/z557.2 (MH⁺), t_(R)=5.65 min.

Example 1012

Synthesized as described in Example 999 using 3-trifluoromethylaniline.LCMS m/z 546.3 (MH⁺), t_(R)=5.74 min.

Example 1013

Synthesized as described above in Example 999 using 3-iodoaniline. LCMSm/z 604.2 (MH⁺), t_(R)=5.81 min.

Example 10144-[1-Methyl-2-(3-phenoxy-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide Step 1. Synthesis of 3-phenoxyphenylisothiocyanate

To a stirring solution of 3-phenoxyaniline (185 mg, 1.0 mmol) in acetone(4.0 mL) at 0° C. was added thiophosgene (0.23 mL, 3.0 mmol) and theresulting reaction maintained for 30 min. The reaction determinedcomplete by TLC (4:1 hexane/EtOAc). The reaction was concentrated,azeotroped with toluene and taken on without further purification.

Step 2. Synthesis of4-[1-Methyl-2-(3-phenoxy-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide

A 1 dram vial was charged with a solution of3-phenoxyphenylisothiocyanate (23 mg, 0.1 mmol), diamine 1 (27 mg, 0.1mmol), and MeOH (0.5 mL) and the reaction was shaken at rt overnight.Methyl iodide (8 uL, 0.13 mmol) was added and the mixture shakenovernight. The reaction was concentrated and the resulting residuepurified on reverse phase HPLC. LCMS m/z 466.3 (MH⁺), t_(R)=2.40 min.

Example 1015

Synthesized as described in Example 1014 step 2 using4-trifluoromethylthiophenylisothiocyanate. LCMS m/z 474.5 (MH⁺),t_(R)=3.76 min.

Example 1016

Synthesized as described in Example 1014 step 2 using3-trifluoromethylthiophenylisothiocyanate. LCMS m/z 474.5 (MH⁺),t_(R)=3.65 min.

Example 1017

Synthesized as described in Example 1014 step 2 using4-1-isothiocyanato-4-methanesulfonyl-benzene, prepared as in step 1.LCMS m/z 452.5 (MH⁺), t_(R)=2.86 min.

Example 1018

Synthesized as described in Example 1014 step 2 using4-(2-isothiocyanato-4-trifluoromethyl-phenoxy)-benzonitrile, prepared asin step 1. LCMS m/z 559.6 (MH⁺), t_(R)=4.22 min.

Example 1019

Synthesized as described in Example 1014 step 2 using2-(2-methoxy-phenoxy)-5-trifluoromethyl-phenylisothiocyanate, preparedas in step 1. LCMS m/z 564.6 (MH⁺), t_(R)=4.42 min.

Example 1020

Synthesized as described in Example 1014 step 2 using2-phenylsulfanyl-phenylisothiocyanate, prepared as in step 1. LCMS m/z482.5 (MH⁺), t_(R)=3.85 ml.

Example 1021

Synthesized as described in Example 1014 step 2 using4-isothiocyanato-3-trifluoromethoxy-benzonitrile, prepared as in step 1.LCMS m/z 483.4 (MH⁺), t_(R)=2.35 min.

Example 1022

Synthesized as described in Example 1014 step 2 using2,4-dibromo-6-fluorophenylisothiocyanate. LCMS m/z 550.3 (MH⁺),t_(R)=3.50 min.

Example 1023

Synthesized as described in Example 1014 step 2 using4-bromo-2-trifluoromethoxy-phenylisothiocyanate. LCMS m/z 537.3 (MH⁺),t_(R)=3.89 min.

Example 1024

Synthesized as described in Example 1014 step 2 usingphenylisothiocyanate. LCMS m/z 374.5 (MH⁺), t_(R)=2.84 min.

Example 1025

Synthesized as described in Example 1014 step 2 using2-phenoxy-phenylisothiocyanate, prepared as in step 1. LCMS m/z 466.5(MH⁺), t_(R)=2.37 min.

Example 1026

Synthesized as described in Example 1014 step 2 using2-methyl-phenylisothiocyanate. LCMS m/z 388.5 (MH⁺), t_(R)=2.99 min.

Example 1027

Synthesized as described in Example 1014 step 2 using2-difluoromethoxy-phenylisothiocyanate. LCMS m/z 440.5 (MH⁺), t_(R)=3.13min.

Example 1028

Synthesized as described in Example 1014 step 2 using2-iodo-phenylisothiocyanate. LCMS m/z 500.4 (MH⁺), t_(R)=2.07 min.

Example 1029

Synthesized as described in Example 1014 step 2 using2,6-diisopropyl-phenylisothiocyanate. LCMS m/z 430.5 (MH⁺), t_(R)=2.27min.

Example 10304-[2-(4-Bromophenyl)-1-methyl-1H-benzimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide

A mixture of diamine 1 (137 mg, 0.36 mmol) and 4-bromobenzaldehyde (66mg, 0.50 mmol) in dry dioxane (2 mL) was heated to 100° C. for 16 h. Thereaction mixture was allowed to cool to rt and was then concentrated.The resulting residue was purified by reverse phase HPLC to furnish 2 asthe TFA salt: LCMS m/z 437.1, t_(R)=2.16 min.

Example 10314-[1-Methyl-2-(4-methylbenzylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide

Prepared as per Example 120b using 4-methylbenzyl thioisocyanate: LCMSm/z 402.2 (MH⁺), t_(R)=1.91 min.

Example 10324-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

Prepared as per Example 371 using amido-1-(3-aminopropyl)pyrrolidine:LCMS m/z 549.5 (MH⁺), t_(R)=2.97 min.

Example 1033(4-Bromophenyl)-[1-methyl-5-(pyridin-4-yloxy)-1H-benzolimidazol-2-yl]-amine

A solution of acid 1 (44 mg, 0.1 mmol) in dry NMP (1 mL) was heated at200° C. for 20 min. The reaction was allowed to cool to rt and the crudereaction mixture was directly purified on reverse-phase HPLC to provide2 as a TFA salt: ¹H NMR (300 MHz, CD3OD) δ 8.67 (d, J=7.4 Hz, 2H), 7.70(d, J=8.5 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.42(d, J=7.4 Hz, 2H), 7.32 (d, J=2.2 Hz, 1H), 7.26 (dd, J=2.2, 8.5 Hz, 1H),3.86 (s, 3H); LCMS m/z 395.0 (MH⁺), t_(R)=1.48 min.

Example 1034

LCMS m/z 359.3 (MH⁺), t_(R)=1.91 min.

Example 1035{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzolimidazol-5-yloxy]-pyridin-2-yl}-methanol

A suspension of t-butyl ester 1 (496 mg, 1.0 mmol) in dry THF (3 mL) wasadded to a stirring suspension of LAH (61 mg, 1.6 mmol) in dry THF (2mL) at −78° C. The reaction was allowed to warm to rt over 3 h. Afterthe reaction was judged complete by LCMS, water (30 ul, 1.7 mmol) andNaF (270 mg, 6.4 mmol) were added and the resulting mixture was stirredvigorously overnight at rt. The crude mixture was filtered throughCelite and the remaining solids were rinsed with EtOAc. The combinedorganic portions were concentrated and a portion of the resultingresidue was purified by reverse-phase HPLC to furnish alcohol 2 as a TFAsalt: ¹H NMR (300 MHz, CD3OD) δ 8.56 (d, J=7.2 Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.33 (m, 3H),7.28 (dd, J=2.2, 8.5 Hz, 1H), 4.86 (app s, 2H), 3.87 (s, 3H); LCMS m/z425.1, t_(R)=1.49 min.

Example 1036(4-Bromophenyl)-[1-methyl-5-(2-methylaminomethyl-pyridin-4-yloxy)-1Hbenzoimidazol-2-yl]-amine General Preparation for Benzyl Amines Step 1.4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxaldehyde

Dry DMSO (0.1 mL, 1.4 mmol) was added to a solution of oxalyl chloride(0.11 mL, 1.3 mmol) in dry THF (2 mL) at −78° C. and the resultingsolution was maintained at −78° C. for 30 min. A solution of alcohol 1in dry THF (2 mL) was then introduced and the resulting reaction wasmaintained at −78° C. for 30 min, then at −50° C. for 45 min.Triethylamine (0.5 mL, 3.6 mmol) was added and the reaction was allowedto warm to rt over 1 h. The reaction was quenched with water andpartitioned with EtOAc. The layers were separated and the aqueousportion was extracted with EtOAc (3×). The combined organic phases werewashed with brine, dried (MgSO₄), and concentrated. The resultingresidue was carried forward without further purification.

Step 2.(4-Bromophenyl)-[1-methyl-5-(2-methylaminomethyl-pyridin-4-yloxy)-1Hbenzoimidazol-2-yl]-amine

Methyl amine (0.3 mL, 0.6 mmol, 2.0 M in MeOH) was added to a solutionof aldehyde 1 in MeOH (1 mL) and the reaction was maintained at rt for 2d. The reaction was acidified by addition of acetic acid (pH=3-4), andan excess of NaBH₃CN was added. The reaction was maintained for 2 d thenconcentrated. The crude reaction mixture was dissolved in EtOAc andpartitioned with aqueous saturated NaHCO3 solution. The layers wereseparated and the aqueous phase was extracted with EtOAc (3 X). Thecombined organic portions were washed with brine, dried (MgSO₄), andconcentrated. The resulting residue was purified by reverse-phase HPLCto afford N-methyl amine 2 as a TFA salt: ¹H NMR (300 MHz, CD₃OD) δ 8.48(d, J=5.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.67 (d, J=9.4 Hz, 1H), 7.43(d, J=8.8 Hz, 2 h), 7.20 (dd, J=2.2, 9.4 Hz, 1H), 7.19 (d, J=2.2 Hz,1H), 7.02 (d, J=2.2, 1H), 6.90 (dd, J=2.2, 5.8 Hz, 1H), 4.27 (s, 2H),3.86 (s, 3H), 2.76 (s, 3H); LCMS m/z 438.5 (MH⁺), t_(R)=1.85 min.

The following tabulated benzyl amines were prepared by the above methodas in Example 1036 using the appropriate amine.

TABLE 14 LCMS TIME Example Structure (MH⁺) m/z t_(R) (min) 1037

549.1 1.62 1038

482.2 1.94 1039

494.1 1.59 1040

468.2 1.87 1041

483.3 1.83 1042

536.2 1.87 1043

552.2 1.84 1044

536.4 1.80 1045

522.3 1.76 1046

550.4 1.80 1047

452.3 2.70* 1048

521.4 3.63* 1049

465.3 2.75* 1050

467.3 2.86* 1051

494.2 1.82 1052

497.2 2.04

Example 1053[5-(2-Aminomethyl-pyridin-4-yloxy)-1-methyl-1H-benzoimidazol-2-yl]-(4-bromophenyl)-amine

LAH (98 mg, 2.5 mmol) was added portionwise to a stirring solution ofoxime 1 (225 mg, 0.5 mmol) in dry THF (3 mL) at 0° C. After addition,the cooling bath was removed and the reaction was allowed to warm to rtovernight. The reaction was quenched by addition of water (0.1 mL), 10%w/w aqueous NaOH solution (0.1 mL), and water (0.3 mL). The resultingslurry was stirred at rt for 1 h and filtered through Celite. Theremaining solids were rinsed with EtOAc and the organic portions werecombined and concentrated. The crude residue was purified byreverse-phase HPLC to provide benzyl amine 2 as a TFA salt: LCMS m/z424.1 (MH⁺), t_(R)=1.87 min.

Example 1054{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl-methyl]-carbamicacid methyl ester

Methyl chloroformate (6 μL, 0.08 mmol) was added to a solution of benzylamine 1 (21 mg, 0.05 mmol) and triethylamine (69 μL, 0.5 mmol) in dryTHF (1 mL) at 0° C. The reaction was maintained at 0° C. for 20 min,then at rt for 2 h. The reaction mixture was concentrated and purifiedby reverse-phase HPLC to provide methyl carbamate 2 as a TFA salt: LCMSm/z 482.2 (MH⁺), t_(R)=1.96 min.

Example 1055N-{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-ylmethyl}acetamide

To a solution of benzyl amine 1 (17 mg, 0.04 mmol) in dry NMP (2 mL) wasadded triethylamine (0.06 mL, 0.4 mmol) and acetic anhydride (0.04 mL,0.4 mmol). The resulting reaction was maintained at rt overnight andpurified directly by reverse-phase HPLC to furnish acetamide 2 as a TFAsalt: LCMS m/z 466.3 (MH⁺), t_(R)=1.78 min.

Example 10564-[2-(3-Ethylphenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide General Preparation forN-(3-Aminopropyl)-pyrrolidinone Amides Step 1:4-Chloro-pyridine-2-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

Acid chloride 1 (2.12 g, 10 mmol) was treated with N-methylmorpholine(4.5 mL, 41 mmol) and N-(3-aminopropyl)-pyrrolidinone 2 (1.6 mL, 11mmol) in dry THF (40 mL). The reaction was maintained overnight andconcentrated. The residue was dissolved in EtOAc and partitioned withwater. The aqueous portion was extracted with EtOAc (3×) and thecombined organic phases were washed with brine, dried (MgSO₄), andconcentrated. The crude residue was purified by Kugelrohr distillation(0.5 mmHg, 170-200° C.) to provide 3.

Step 2: 4-(4-Methylamino-3-nitrophenoxy)-pyridine-2-carboxylic acid[3-(2-oxo-pyrrolidin-yl)-propyl]-amide

Prepared as per Example 120b with the appropriate substitutions. Amide 3can be purified by flash chromatography (95:5 CH₂Cl₂-MeOH). It can alsobe further purified by recrystallization from MeCN.

Step 3: 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid[3-(2-oxo-pyrrolidin-yl)-propyl]-amide

Prepared as per Example 120b.

Step 4:4-[2-(3-Ethylphenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide

Prepared as per Example 120b to provide benzimidazole 2 as a TFA salt:LCMS m/z 513.3 (MH⁺), t_(R)=2.22 min.

Example 1057

Prepared as per Example 1056: LCMS m/z 563.2 (MH⁺), t_(R)=2.15 min.

Example 1058

Prepared as per Example 1056: LCMS t_(R)=585.3 (MH⁺), t_(R)=2.55 min.

Example 1059

Prepared as per Example 1056: LCMS m/z 563.2 (MH⁺), t_(R)=2.50 min.

The following additional compounds were prepared following theprocedures of the indicated Examples:

TABLE 15 Ex- Synthe- am- sized as ple Structure Name MH+ in Ex.: 1060

N-methyl-4-[(2-{[3-(2-methyl- pyridin-4-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 451.5 702 1061

N-methyl-4-[(1-methyl-6- (methyloxy)-2-{[3-(2-methyl-pyridin-4-yl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 495.6 702 1062

N-methyl-4-{[2-({3-[3-(tri- fluoromethyl)pyridin-4-yl]-phenyl}amino)-1H-benz- imidazol-5-yl]oxy}pyridine-2- carboxamide 505.5702 1063

N-methyl-4-{[1-methyl-6- (methyloxy)-2-({3-[3-(trifluoro-methyl)pyridin-4-yl]phenyl}- amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide 549.5 702 1064

4-[(2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 455.5 702 1065

4-{[2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide499.5 702 1066

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 469.5 702 1067

4-{[2-({3-(2-fluoropyridin-4-yl)- 4-[(trifluoromethyl)oxy]-phenyl}amino)-1H-benz- imidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide 539.5 702 1068

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-hydroxyethyl)-pyridine-2-carboxamide 513.5 483 1069

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carbox- amide 594.7 483 1070

N-[2-(dimethylamino)ethyl]-4- [(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 540.6 483 1071

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide 582.6 483 1072

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2,2,2-trifluoroethyl)-pyridine-2-carboxamide 551.5 483 1073

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide 581.7 483 1074

N-[2-(acetylamino)ethyl]-4-[(2- {[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 554.6 483 1075

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-piperidin-1-ylethyl)-pyridine-2-carboxamide 580.7 483 1076

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-[1-(1-methylethyl)-azetidin-3-yl]pyridine-2-carbox- amide 566.7 636 1077

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-(methyloxy)phenyl]methyl}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 498.5636 1078

N-methyl-4-({1-methyl-2-[(4- methylphenyl)methyl]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 387.5 636 1079

N-methyl-4-[(1-methyl-2-{[4- (methyloxy)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 403.5 636 1080

N-methyl-4-[(1-methyl-2-{[4-(1- methylethyl)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 415.5 636 1081

N-methyl-4-{[1-methyl-2-({4- [(trifluoromethyl)oxy]phenyl}methyl)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 457.4 636 1082

4-({2-[(4-chlorophenyl)methyl]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 407.9 636 1083

N-methyl-4-[(1-methyl-2-{[4- (trifluoromethyl)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 441.4 636 1084

4-{[2-{[3-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide460.5 703 1085

N-methyl-4-{[1-methyl-2-{[3- (1-methylethyl)phenyl]amino}-6-(methyloxy)-1H-benz- imidazol-5-yl]oxy}pyridine-2- carboxamide 446.5703 1086

N-methyl-4-[(2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2- carboxamide 402.5 1 1087

4-[(2-{[4-(1,1-dimethylethyl)-3- (2-fluoropyridin-4-yl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 525.6 702 1088

4-{[2-{[4-(1,1-dimethylethyl)-3- (2-fluoropyridin-4-yl)phenyl]-amino}-1-methyl-6-(methyl- oxy)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 555.6 702 1089

4-[(2-{[4-(1,1-dimethylethyl)-3- (2-fluoropyridin-4-yl)phenyl]-amino}-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 511.6702 1090

4-{[2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-6-(methyloxy)-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 513.5 702 1091

4-[(2-{[3-(2,6-dimethylpyridin- 4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 479.6 702 1092

4-[(2-{[3-(2,6-dimethylpyridin- 4-yl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 465.5 702 1093

4-{[2-{[3-(2,6-dimethylpyridin- 4-yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide509.6 702  1094a

N-methyl-4-({1-methyl-2-[(4- methyl-3-thien-2-ylphenyl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 470.6 702 1094b

N-methyl-4-({1-methyl-2-[(3- thien-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 456.5 702

General Preparation for Phenolic Benzimidazoles3-Amino-4-methylaminophenol

Diamine 2 prepared as per Example 120b from nitroaniline 1.

Example 1095 2-(3-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-ol

Benzimidazole 2 was prepared as per Example 120b: LCMS m/z 318.1 (MH⁺),t_(R)=2.07 min.

Example 1096

LCMS m/z 332.1 (MH⁺), t_(R)=2.22 min

Example 1097

LCMS m/z 366.1 (MH⁺), t_(R)=2.13 min

Example 1098

LCMS m/z 340.2 (MH⁺), t_(R)=2.39 min

Example 1099 Preparation of Symmetrical bis-Benzimidazoles Step 1:4,4′-dimethylamino-3,3′-dinitro diphenyl ether

Diphenyl ether 2 was prepared using the method described in Example120b: ¹H NMR (300 MHz, CDCl₃) δ 7.98 (br s, 2H), 7.75 (d, J=3.0 Hz, 2H),7.29 (app d, J=3.0 Hz, 1H), 6.87 (d, J=9.5 Hz, 2H), 3.05 (d, J=5.2 Hz,6H).

Step 2: 4,4′-dimethylamino-3,3′-diamino diphenyl ether

Tetramine 2 was prepared as per Example 120b: ¹H NMR (300 MHz, CDCl₃) δ6.59 (d, J=8.5 Hz, 2H), 6.47 (dd, J=2.8, 8.5 Hz, 2H), 6.41 (d, J=2.8 Hz,2H), 3.40 (br s, 4H), 3.06 (br s, 2H), 2.84 (d, J=5.5 Hz, 6H).

Example 1100bis-5-[2-(3-Bromophenylamino)-1-methyl-1H-benzoimidazole]-ether

Prepared as per Example 120b: LCMS m/z 617.1 (MH⁺), t_(R)=2.27 min

Example 1101

Prepared as per Example 120b: LCMS m/z 573.4 (MH⁺), t_(R)=2.78 min

Example 1102

Prepared as per Example 120b: LCMS t/z 661.2 (MH⁺), t_(R)=2.83 min

Example 1103

Prepared as per Example 120b: LCMS m/z 545.4 (MH⁺), t_(R)=2.73 min

Example 1104

Prepared as per Example 120b: LCMS m/z 461.3 (MH⁺), t_(R)=1.98 min

Example 1105 Preparation of Benzo Derivatives2-(N-Phthalimido)-4-fluoronitrobenzene

A suspension of 2,4 difluoronitrobenzene (15.9 g, 100 mmol) andpotassium phthalimide (16.5 g, 100 mmol) was stirred in dry NMP (50 mL)for 3 d. The reaction solution was poured into MTBE and the resultingprecipitate was collected by filtration. The solids were washed withMTBE (3×) and the mother liquor was extracted with MTBE (3×). Thecombined organic portions were washed with water (3×) and concentratedto furnish a yellow solid which was combined with the initial crop ofprecipitate. The combined crude solid was purified by recrystallizationfrom hot toluene, and the crystals were washed with cold MTBE: ¹H NMR(300 MHz, d⁶-DMSO) δ 8.31 (dd, J=5.2, 9.1 Hz, 1H), 7.98 (m, 4H), 7.69(dd, J=2.8, 9.1 Hz, 1H), 7.62 (ddd, J=1.7, 2.8, 7.7 Hz, 1H).

Example 1106 2-(N-Phthalimido)-4-phenoxynitrobenzene

2-(N-Phthalimido)-4-phenoxynitrobenzene 2 was prepared using a similarprocedure employed in Example 120b.

Example 1107 2-(N-Phthalimido)-4-phenoxyaniline

2-(N-Phthalimido)-4-phenoxyaniline 2 was obtained through the reductionof 2-(N-phthalimido)-4-phenoxynitrobenzene 1 as described in Example120b.

Example 1108 N-[2-(N-Phthalimido)-4-phenoxy-phenyl]-formamide

A mixture of formic acid (0.12 mL, 5.3 mmol) and acetic anhydride (0.24mL, 2.5 mmol) was heated to 60° C. for 2 h. After allowing to cool tort, a solution of aniline 1 (387 mg, 1.0 mmol) in dry THF (1 mL) wasadded and the reaction was maintained overnight. The reaction wasconcentrated and the resulting crude residue was directly used in thenext step.

Example 1109 N-Methyl-[2-(N-phthalimido)-4-phenoxy]-aniline

A solution of formamide 1 was treated with BH₃-DMS solution (2.0 M inCH₂Cl₂, 0.5 mL, 1.0 mL) and the reaction was allowed to warm to rtovernight. The reaction was concentrated and the resulting residue wasdissolved in EtOAc. The solution was partitioned with saturated aqueousNaHCO₃ solution and the layers were separated. The aqueous phase wasextracted with EtOAc (3×) and the combined organics phases were washedwith brine, dried (MgSO₄), adsorbed onto SiO₂ and purified by flashchromatography (4:1 hexanes-EtOAc) to furnish 2 as a colorless residue.

Example 1110 N1-Methyl-4-phenoxybenzene-1,2-diamine

Hydrazine monohydrate (0.13 mL, 2.7 mmol) was added to a solution ofphthalimide 1 (134 mg, 0.39 mmol) in ethanol (4 mL). The reaction wasmaintained overnight at rt and then was filtered through Celite. Thefilter cake was rinse with EtOAc (3×) and the organic portions werecombined and concentrated to give diamine 2 which was carried forwardwithout further purification: LCMS m/z 215.1 (MH⁺), t_(R)=1.77 min.

Example 1111 Synthesis of(4-Bromophenyl)-(1-methyl-5-phenoxy-1H-benzoimidazol-2-yl)-amine

Benzimidazole 2 was prepared as per Example 120b: ¹H NMR (300 MHz,CD₃OD) δ 7.68 (app ddd, J=2.9, 4.9, 8.8 Hz, 2H), 7.53 (app d, J=8.8 Hz,1H), 7.41 (app ddd, J=2.9, 4.9, 8.8 Hz, 2H), 7.40 (app ddd, J=1.0, 2.0,8.5 Hz, 2 h), 7.24 (app ddd, J=1.0, 2.0, 8.5 Hz, 1H), 7.07 (app dd,J=2.2, 8.8 Hz, 1H), 7.00 (app d, J=2.2 Hz, 1H), 7.00 (app ddd, J=1.0,2.0, 8.5 Hz, 2H), 3.82 (s, 3H); LCMS m/z 394.0 (MH⁺), t_(R)=2.36 min.

Example 1112

A solution of 1 in MeCN was treated with aqueous 1 N HCl and freezedried. The resulting residue was purified by reverse-phase HPLC toprovide vinyl chloride 2 as a TFA salt: LCMS m/z 434.2 (MH⁺), t_(R)=2.48min.

Example 11134-[2-(3-Furan-3-yl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methyl amide

A solution of Pd(OAc)₂ (4.5 mg, 0.02 mmol) and triphenylphosphine (13.1mg 0.05 mmol) in dry NMP (1 mL) was stirred at rt for 20 min. Aryliodide 1 (100 mg, 0.2 mmol), 3-furyl boronic acid (45 mg, 0.4 mmol), andtriethylamine (0.11 mL, 0.8 mmol) were added and the resulting solutionwas degassed and purged with Ar. The reaction was heated to 100° C. for2 h; LCMS indicated no conversion. The reaction was allowed to cool tort under Ar and Pd(dppf)Cl₂CH₂Cl₂ and diisopropylethylamine (0.14 mL)were added. The reaction was heated to 100° C. and maintained overnight.The reaction was allowed to cool to rt and LCMS indicated completeconversion. The reaction was partitioned between saturated aqueousNaHCO₃ solution and EtOAc and the resulting mixture filtered throughCelite. The remaining solids were washed with water and EtOAc. Thecombined rinsings were partitioned and separated. The aqueous phase wasextracted with EtOAc (3×) and the combined organic portions were washedwith saturated aqueous Na₂CO₃, brine, dried (MgSO₄), and concentrated.The crude residue was purified by reverse-phase HPLC to furnish 2 as aTFA salt: LCMS m/z 440.3 (MH⁺), t_(R)=2.35 min.

Example 1114

Prepared as per Example 120b.

Example 1115

Prepared as per Example 120b.

Example 1116 Raf/Mek Filtration Assay Buffers

Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCl₂, 0.1 mM EDTA, 1 mM DTT

Wash buffer: 25 mM Hepes, pH 7.4, 50 mM sodium pyrophosphate, 500 mMNaCl

Stop reagent: 30 mM EDTA

Materials

Raf, active: Upstate Biotech #14-352 Mek, inactive: Upstate Biotech#14-205 ³³P-ATP: NEN Perkin Elmer #NEG 602 h 96 well assay plates:Falcon U-bottom polypropylene plates #35-1190 Filter apparatus:Millipore #MAVM 096 OR 96 well filtration plates: Millipore Immobilon 1#MAIP NOB Scintillation fluid: Wallac OptiPhase “SuperMix” #1200-439

Assay Conditions

Raf approximately 120 μM

Mek approximately 60 nM

³³P-ATP 100 nM

Reaction time 45-60 minutes at room temperature

Assay Protocol

Raf and Mek were combined at 2× final concentrations in assay buffer (50mM Tris, pH 7.5, 15 mM MgCl₂. 0.1 mM EDTA and 1 mM DTT) and dispensed 15μl per well in polypropylene assay plates (Falcon U-bottom polypropylene96 well assay plates #35-1190. Background levels are determined in wellscontaining Mek and DMSO without Raf.

To the Raf/Mek containing wells was added 3 μl of 10× of a raf kinaseinhibitor test compound diluted in 100% DMSO. The raf kinase activityreaction was started by the addition of 12 μl per well of 2.5× ³³P-ATPdiluted in assay buffer. After 45-60 minutes, the reactions were stoppedwith the addition of 70 μl of stop reagent (30 mM EDTA). Filtrationplates were pre-wetted for 5 min with 70% ethanol, and then rinsed byfiltration with wash buffer. Samples (90 μl) from the reaction wellswere then transferred to the filtration plates. The filtration plateswere washed 6× with wash buffer using Millipore filtration apparatus.The plates were dried and 100 μl per well of scintillation fluid (WallacOptiPhase “SuperMix” #1200-439) was added. The CPM is then determinedusing a Wallac Microbeta 1450 reader.

Example 1117 Assay 2: Biotinylated Raf Screen

In Vitro Raf Screen

The activity of various isoforms of Raf serine/threonine kinases can bemeasured by providing ATP, MEK substrate, and assaying the transfer ofphosphate moiety to the MEK residue. Recombinant isoforms of Raf wereobtained by purification from sf9 insect cells infected with a human Rafrecombinant baculovirus expression vector. Recombinant kinase inactiveMEK was expressed in E. coli and labeled with Biotin post purification.For each assay, test compounds were serially diluted in DMSO then mixedwith Raf (0.50 nM) and kinase inactive biotin-MEK (50 nM) in reactionbuffer plus ATP (1 uM). Reactions were subsequently incubated for 2hours at room temperature and stopped by the addition of 0.5 M EDTA.Stopped reaction mixture was transferred to a neutradavin-coated plate(Pierce) and incubated for 1 hour. Phosphorylated product was measuredwith the DELFIA time-resolved fluorescence system (Wallac), using arabbit anti-p-MEK (Cell Signaling) as the primary antibody and europiumlabeled anti-rabbit as the secondary antibody. Time resolvedfluorescence was read on a Wallac 1232 DELFIA fluorometer. Theconcentration of each compound for 50% inhibition (IC₅₀) was calculatedby non-linear regression using XL Fit data analysis software.

Using the procedures of Examples 1116 or 1117, the compounds of Examples1-1094 were shown to have a raf kinase inhibitory activity at an IC₅₀ ofless than 5 μM.

While the preferred embodiment of the invention has been illustrated anddescribed, it will be appreciated that various changes can be madetherein without departing from the spirit and scope of the invention.

1. A compound of the formula (I):

wherein, X₁ and X₂ are independently selected from ═N—, —O— or —S—,provided that when X₁ is ═N—, X₂ is —O— or —S—; when X₂ is ═N—, X₁ is—O— or —S—; and X₁ and X₂ are not both O or S; Y is O or S; A₁ issubstituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl,heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, orheteroarylarylalkyl; A₂ is substituted or unsubstituted heteroaryl; R₁is O or H, and R₂ is NR₅R₆ or hydroxyl; or R₁ is taken together with R₂to form a substituted or unsubstituted heterocycloalkyl or heteroarylgroup; wherein, the dashed line represents a single or double bond; R₃is hydrogen, halogen, loweralkyl, or loweralkoxy; R₅ and R₆ areindependently selected from hydrogen, and substituted or unsubstitutedalkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, andheteroarylalkyl; or R₅ and R₆ are taken together to form substituted orunsubstituted heterocyclo or heteroaryl; and the pharmaceuticallyacceptable salts, esters and prodrugs thereof.
 2. A compound of claim 1wherein X₁ is —O— or —S—, and X₂ is ═N—.
 3. A compound of claim 1wherein Y is O.
 4. A compound of claim 1 wherein A₁ is selected from thegroup consisting of substituted or unsubstituted phenyl, pyridyl,pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl,heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl,chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl,nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl,dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene,thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl,acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl,phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl,trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.
 5. Acompound of claim 1 wherein A₂ is substituted or unsubstituted pyridyl.6. A compound of claim 1 wherein R₁ is O and the dashed line representsa single or double bond.
 7. A compound of claim 1 wherein R₂ is NR₅R₆,R₅ is hydrogen and R₆ is selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 8. A compound of claim 1wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 9. A compound ofclaim 1 wherein R₃ is loweralkoxy.
 10. A compound of claim 1 wherein R₃is methoxy.
 11. The compound of claim 1 wherein R₁ is O, R₂ is NR₅R₆, R₅is H, and R₆ is methyl.
 12. A compound of the formula (III):

wherein X is O or S; A₁ is substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, heteroarylarylalkyl; A₂ is substituted or unsubstitutedheteroaryl; R₁ is O and R₂ is NR₅R₆; or R₁ is taken together with R₂ toform a substituted or unsubstituted heterocycloalkyl or heteroarylgroup; wherein, the dashed line represents a single or double bond; R₃is hydrogen, halogen, loweralkyl, or loweralkoxy; R₅ and R₆ areindependently selected from hydrogen, and substituted or unsubstitutedalkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, andheteroarylalkyl; or R5 and R6 are taken together to form substituted orunsubstituted heterocyclo or heteroaryl; and the pharmaceuticallyacceptable salts, esters and prodrugs thereof.
 13. A compound of claim12 wherein X is O.
 14. A compound of claim 12 wherein A₁ is selectedfrom the group consisting of substituted or unsubstituted phenyl,pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl,heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl,chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl,nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl,dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene,thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl,acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl,phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl,trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-l′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 15.A compound of claim 12 wherein A₂ is substituted or unsubstitutedpyridyl.
 16. A compound of claim 12 wherein R₁ is 0 and the dashed linerepresents a single or double bond.
 17. A compound of claim 12 whereinR₂ is NR₅R₆, R₅ is hydrogen and R₆ is selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 18. A compound of claim12 wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 19. A compound ofclaim 12 wherein R₃ is loweralkoxy.
 20. A compound of claim 12 whereinR₃ is methoxy.
 21. A compound of claim 12 wherein R₁ is O, R₂ is NR₅R₆,R₅ is H, and R₆ is methyl.
 22. A compound of the formula (IV):

wherein X is O or S; Y is O or S; A₁ is substituted or unsubstitutedcycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclicarylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, heteroarylarylalkyl; R₁ is O and R₂ is NR_(S) R₆; or R₁ istaken together with R₂ to form a substituted or unsubstitutedheterocycloalkyl or heteroaryl group; wherein, the dashed linerepresents a single or double bond; R₃ is hydrogen, halogen, loweralkyl,or loweralkoxy; R₅ and R₆ are independently selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;and the pharmaceutically acceptable salts, esters and prodrugs thereof.23. A compound of claim 22 wherein Y is O.
 24. A compound of claim 22wherein A₁ is selected from the group consisting of substituted orunsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl,heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl,iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl,alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl,trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl,cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl,trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-l′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 25.A compound of claim 22 wherein R₁ is 0 and the dashed line represents asingle or double bond.
 26. A compound of claim 22 wherein R₂ is NR₅R₆,R₅ is hydrogen and R₆ is selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 27. A compound of claim22 wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 28. A compound ofclaim 22 wherein R₃ is loweralkoxy.
 29. A compound of claim 22 whereinR₃ is methoxy.
 30. A compound of claim 22 wherein R₁ is O, R₂ is NR₅R₆,R₅ is H, and R₆ is methyl.
 31. A compound of the formula (V):

wherein X is O or S; A₁ is substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, heteroarylarylalkyl; R₁ is O and R₂ is NR₅R₆; or R₁ istaken together with R₂ to form a substituted or unsubstitutedheterocycloalkyl or heteroaryl group; wherein, the dashed linerepresents a single or double bond; R₃ is hydrogen, halogen, loweralkyl,or loweralkoxy; R₅ and R₆ are independently selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;and the pharmaceutically acceptable salts, esters and prodrugs thereof.32. A compound of claim 31 wherein A₁ is selected from the groupconsisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl,phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl,heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl,bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl,4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl,dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate,alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl,biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl,alkylbromophenyl, alkylchlorophenyl, alkylfluorophenyl,trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl,2,3-dihydroindenyl, tetralinyl, trifluorophenyl,(trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl,N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl,2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl,bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl,pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl,4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl,bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-l′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 33.A compound of claim 31 wherein R₁ is 0 and the dashed line represents asingle or double bond.
 34. A compound of claim 31 wherein R₂ is NR₅R₆,R₅ is hydrogen and R₆ is selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 35. A compound of claim31 wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 36. A compound ofclaim 31 wherein R₃ is loweralkoxy.
 37. A compound of claim 31 whereinR₃ is methoxy.
 38. A compound of claim 31 wherein R₁ is O, R₂ is NR₅R₆,R₅ is H, and R₆ is methyl.
 39. A composition comprising an amount of acompound of claim 1 effective to inhibit Raf activity in a human oranimal subject when administered thereto, together with apharmaceutically acceptable carrier.
 40. A composition of claim 39 whichfurther comprises at least one additional agent for the treatment ofcancer.
 41. A composition of claim 40 in which the at least oneadditional agent for the treatment of cancer is selected fromirinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorincarboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vincaalkaloids, imatinib, anthracyclines, rituximab and trastuzumab.
 42. Amethod of inhibiting Raf kinase activity in a human or animal subject,comprising administering to the human or animal subject a compositioncomprising an amount of a compound of claim 1 effective to inhibit Rafkinase activity in the human or animal subject.
 43. A method fortreating a cancer disorder in a human or animal subject, comprisingadministering to the human or animal subject a composition comprising anamount of a compound of claim 1 effective to inhibit Raf kinase activityin the human or animal subject.
 44. A method of claim 43 which furthercomprises administering to the human or animal subject at least oneadditional agent for the treatment of cancer.
 45. A method of claim 44in which the at least one additional agent for the treatment of canceris selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil,leucovorin carboplatin, cisplatin, taxanes, tezacitabine,cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximaband trastuzumab.
 46. A method for treating a hormone dependent cancerdisorder in a human or animal subject, comprising administering to thehuman or animal subject a composition comprising an amount of a compoundof claim 1 effective to inhibit Raf kinase activity in the human oranimal subject.
 47. A method of claim 46 wherein the hormone dependentcancer is breast cancer or prostate cancer.
 48. A method of claim 46which further comprises administering to the human or animal subject atleast one additional agent for the treatment of cancer.
 49. A method ofclaim 48 in which the at least one additional agent for the treatment ofcancer is selected from irinotecan, topotecan, gemcitabine,5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,tezacitabine, cyclophosphamide, vinca alkaloids, imatinib,anthracyclines, rituximab and trastuzumab.
 50. A method for treating ahematological cancer disorder in a human or animal subject, comprisingadministering to the human or animal subject a composition comprising anamount of a compound of claim 1 effective to inhibit Raf kinase activityin the human or animal subject.
 51. A method of claim 50 which furthercomprises administering to the human or animal subject at least oneadditional agent for the treatment of cancer.
 52. A method of claim 51in which the at least one additional agent for the treatment of canceris selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil,leucovorin carboplatin, cisplatin, taxanes, tezacitabine,cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximaband trastuzumab.